Two convergent approaches toward novel carbocyclic C-nucleosides

Article abstract of DOI:10.1055/s-0030-1258271

Two convergent methodologies for construction of novel carbocyclic C-nucleosides allowing the syntheses of derivatives with uracil heterobase substituted at the position C-5 as well as C-6 were developed. The crucial step of the first methodology was the

Full text of DOI:10.1055/s-0030-1258271

PAPER
4119
Two Convergent Approaches toward Novel Carbocyclic C-Nucleosides
Convergent
A
ppr
a
oaches toC
d
arbocyclic
C
i
-Nucle
m
osides Nencka, Michal Šála, Milan Dejmek, Martin Dračínský, Antonín Holý, Hubert Hřebabecký*
Centre for New Antivirals and Antineoplastics, Institute of Organic Chemistry and Biochemistry Academy of Sciences of the
Czech Republic, v.v.i., Gilead Sciences & IOCB Research Center, 166 10 Prague 6, Czech Republic
Fax +420(2)20183560; E-mail: nencka@uochb.cas.cz
Received 3 August 2010; revised 10 August 2010
able model for further investigation of novel, more direct
routes toward this type of compounds.
Abstract: Two convergent methodologies for construction of novel
carbocyclic C-nucleosides allowing the syntheses of derivatives
with uracil heterobase substituted at the position C-5 as well as C-6
were developed. The crucial step of the first methodology was the
reaction of (6-chloro-2,4-dimethoxypyrimidin-5-yl)lithium, the nu-
cleobase precursor, with suitable ketones, the carbocyclic pseu-
dosugar precursors. The second approach was based on the copper-
catalyzed cross-coupling between magnesiated pyrimidine and ap-
propriate allyl chlorides. These methodologies were applied for the
synthesis of novel carbocyclic C-nucleosides bearing cyclohexene
or cyclohexane as a pseudosugar.
We decided to explore the possibilities of direct connec-
tion of a pyrimidine base and a cyclohexane ring to avoid
the difficulties caused by the base building. As a result of
this effort, we have developed two convergent synthetic
methods for the preparation of carbocyclic C-nucleosides.
One of them led to the uracil derivatives with the cyclo-
hexane (or cyclohexene) ring attached at the C-5 position
and the other at the C-6 position.
Key words: carbocyclic C-nucleosides, convergent approach,
uracil, pyrimidines, cross-coupling reaction
The former synthetic route started from cyclohex-3-ene-
1,1-diyldimethanol (1) by a slightly modified procedure
of tritylation and subsequent epoxidation as described by
Mikhailov and co-workers.9 The cyclohexanols 4 and 5
were synthesized by reduction of epoxide 3 with lithium
aluminum hydride in diethyl ether. The reduction pro-
ceeded smoothly in good yield and the resolution of iso-
mers 4 and 5 was performed by simple column
chromatography. Further oxidation to ketones 6 and 7 was
performed by pyridinium dichromate (PDC) in N,N-di-
methylformamide (Scheme 1).
Carbocyclic nucleosides1,2 and C-nucleosides2,3 belong to
the very important concepts in the development of novel
substances for biomedical applications. Carbocyclic C-
nucleosides originated from the combination of these two
approaches. The characteristic feature of all forenamed
nucleoside analogues is the enhanced hydrolytic stability
of the bond between nucleobase and sugar (pseudosugar)
moiety. Although the first attempts to synthesize carbocy-
clic C-nucleosides dates back to the 1960s,4 only few ex-
amples of such compounds have been prepared and tested
for biological activity since then.5 Rao and co-workers6
showed that 9-deazaneplanocin A exerts moderate anti-
HIV activity and found that several pyrimidine bases
bearing cyclopentenyl analogues of C-nucleosides are an-
tivirally active. Furthermore, several other variously mod-
ified derivatives with carbocyclic pseudosugar bonded to
the heterocyclic base by carbon–carbon bond were identi-
fied to possess interesting biological properties.7
RO
TrO
TrO
O
b
RO
a
1 R = H
2 R = Tr
3
c
O
OH
TrO
TrO
TrO
TrO
d
6
7
4
+
The crucial drawback of all the mentioned carbocyclic C-
nucleoside syntheses is the traditional linear approach. In
most cases the nucleobase was built up in several steps on
the carbocyclic pseudosugar. Therefore, novel straightfor-
ward synthetic pathways towards carbocyclic C-nucleo-
sides are still necessary.
TrO
TrO
TrO
TrO
d
O
OH
5
Scheme 1 Reagents and conditions: a) TrCl, pyridine, 100 °C,
86%; b) MCPBA, CH2Cl2, 0 °C, 75%; c) LiAlH4, Et2O, 40% of 4,
37% of 5; d) PDC, DMF, 88% of 6, 86% of 7.
In this paper, we continue our investigation in the field of
carbanucleosides8 by the synthesis of novel cyclohexyl
and cylohexenyl C-nucleosides with pyrimidine nucleo-
bases. Cyclohexane used in this study seems to be a suit-
The key step of this pathway was the reaction of these ke-
tones with (6-chloro-2,4-dimethoxypyrimidin-5-yl)lithi-
um (9) prepared form 6-chloro-2,4-dimethoxypyrimidine
(8) and n-BuLi.10 Thermal stability of the organolithium
compound 9 was demonstrated on a simple study per-
formed as a yield comparison of its reaction with benzal-
dehyde after stirring the lithiated species for appropriate
SYNTHESIS 2010, No. 23, pp 4119–4130
x
x.
x
x
.
2
0
1
0
Advanced online publication: 28.09.2010
DOI: 10.1055/s-0030-1258271; Art ID: Z19910SS
© Georg Thieme Verlag Stuttgart · New York

4120
R. Nencka et al.
PAPER
time at defined temperature. As depicted in Table 1 and Treatment of the ketone 6 with organolithium species 9
Figure 1, the stability showed an extreme loop between resulted in the formation of expected adduct 10 in very
0 and –25 °C.
good yield when the reaction temperature was kept around
–30 °C. On heating the intermediate 10 with aqueous hy-
drochloric acid in a mixture of tetrahydrofuran and 1,4-di-
oxane, removal of protecting groups as well as
elimination of tertiary hydroxy group occurred, forming
products 11 and 12 in approximately 6:1 ratio. The pre-
vailing isomer 11 was partially separated by crystalliza-
tion and the other isomer 12 and a further portion of 11
was isolated by preparative HPLC. The mixture of iso-
mers 11/12, isolated by standard column chromatography,
was utilized in the next step where the double bond and
the chlorine atom were removed by catalytic hydrogena-
tion to yield the pseudouridine derivative 13.
In a different approach, the precursor 10 can be hydroge-
nated first to afford the derivative 14, and then deprotect-
ed and eliminated. Surprisingly, the main product of this
deprotection/elimination procedure was the bicyclic com-
pound ( )-15 resulting from the acid-catalyzed intramo-
lecular etherification rather than the product of
elimination (Scheme 2). This empirical observation can
be explained by significantly higher sterical hindrance of
the reaction center in the carbocationic transition state in
the presence of the chlorine atom on the pyrimidine moi-
ety.
Figure 1 Time-dependence of thermal stability of (4-chloro-2,6-di-
methoxypyrimidin-5-yl)lithium (9) in THF; x-axis refers to the reac-
tion temperature (°C), y-axis refers to the time of stirring (h), z-axis
refers to the yields obtained from the reaction with benzaldehyde (%)
Table 1 Time-Dependence of Thermal Stability of the Organolithi-
um 9 in THFa
Time of stirring (h)
Temperature of stirring (°C)
–75
–25
0
25
The ketone 7 underwent similar procedure as its counter-
part. The deprotection/elimination step afforded only one
product 17 due to the symmetry of the starting material;
the transformation proceeded with an excellent yield. Hy-
drogenation of this intermediate gave the final compound
18. Also, the removal of the chlorine atom from the sub-
strate 16 was similarly successful (Scheme 3). In contrast
to the other isomer, the treatment of substrate 19 with hy-
drochloric acid in tetrahydrofuran–1,4-dioxane gave the
elimination product 20. The building blocks for the later
methodology of derivatization of uracils and their ana-
logues at position C-6 were also obtained from compound
2
87%
86%
84%
78%
70%
43%
16%
0.1%
0%
0.5%
0%
0%
4.5
8.5
a A solution of 9 was prepared by treatment of 8 in THF with n-BuLi
for 30 min at –75 °C and transferred to the vessels kept at the appro-
priate temperatures and also to the reference vessel containing 3 equiv
of benzaldehyde in THF and stirred for additional 1 h at –75 °C; yield
88%. The samples, took at the defined intervals, were treated with 3
equiv of benzaldehyde in THF for 1 h at –75 °C as well. Yields were
determined by GC-MS after usual workup.
OMe
O
O
O
N
HN
HN
HN
MeO
N
Cl
O
NH
Cl
O
NH
Cl
O
NH
8
HO
HO
HO
HO
HO
HO
d
a
+
OMe
11
12
13
Li
N
c
MeO
N
Cl
9
MeO
MeO
H
N
O
N
HO
10
HO
14
N
N
O
OMe
b
TrO
TrO
TrO
TrO
f
OMe
e
NH
6
N
HO
Cl
O
15
Scheme 2 Reagents and conditions: a) n-BuLi, THF, –75 °C; b) 9, THF, < –20 °C, 82%; c) HCl, THF, 1,4-dioxane, 56% of 11, 11% of 12;
d) H2, Pd(OH)2/C, MeOH, 87%; e) H2, Pd(OH)2/C, Et3N, EtOH, 94%; f) HCl, THF, 1,4-dioxane, 58%.
Synthesis 2010, No. 23, 4119–4130 © Thieme Stuttgart · New York

PAPER
Convergent Approaches to Carbocyclic C-Nucleosides
4121
OMe
N
N
MeO
O
O
TrO
TrO
HO
HO
NH
NH
HO
HO
NH
NH
a
b
c
7
Cl
O
O
OH
Cl
16
17
OMe
18
d
N
MeO
N
O
TrO
TrO
HO
HO
NH
NH
e
O
OH
19
20
Scheme 3 Reagents and conditions: a) 9, THF, < –20 °C, 89%; b) HCl, THF, 1,4-dioxane, 70%; c) H2, Pd(OH)2/C, MeOH, 89%; d) H2,
Pd(OH)2/C, Et3N, EtOH, 98%; e) HCl, THF, 1,4-dioxane, 49%.
1. The crucial allylic intermediates 23 and 24 were pre- cinimide.12 This method proved very effective for forma-
pared from the epoxide 22, obtained from 1 by simple tion of such allylic substrates and afforded excellent
benzoylation19 and epoxidation, by Lewis acid induced yields of desired products. In contrast to comparable allyl
rearrangement11 on treatment with TMSOTf and DBU, bromides and allyl iodides, these products can be chro-
and subsequent hydrolysis of the formed trimethylsilyl matographed on silica gel and stored for several weeks
ether by dilute hydrochloric acid.
without significant loss of quality. The allyl iodide 28,
prepared by the reaction of allyl alcohol with in situ gen-
erated anhydrous hydroiodic acid,13 was obtained in ex-
cellent yield. However, this compound decomposes
rapidly and cannot be stored and hence was used in the
next step immediately after preparation (Scheme 4). Also,
the mixtures of isomeric allyl bromides was prepared di-
rectly by reaction of cyclohexane derivative 2 or 21 with
N-bromosuccinimide in CCl4 in the presence of AIBN.
The reactions proceeded smoothly in very good yield. Un-
fortunately, these mixtures could not be separated (or
even purified) by chromatography and their further reac-
tions resulted in the hardly separable mixtures of coupling
products.
The allylic alcohols 23 and 24 were easily separated by
column chromatography and obtained in good yields in al-
most 1:1 ratio (Scheme 4). Since the hydroxy group is a
very poor leaving group, the obtained alcohols were trans-
formed into various allylic substrates traditionally used in
the coupling reactions with organometallic compounds.
RO
BzO
BzO
O
b
RO
a
1 R = H
21 R = Bz
22
c
The starting pyrimidine iodides, 4-iodo-2,6-dimethoxy-
pyrimidine (33)14 and 4-iodo-2,6-dimethoxy-5-methylpy-
rimidine (34), were prepared in two steps from
appropriate trichloropyrimidines (Scheme 5). The chlo-
rine atoms were substituted by iodine on treatment with
aqueous hydroiodic acid. This reaction proceeds in good
yields but the workup is somewhat tricky. The product
should be collected only by filtration, washed with water
BzO
BzO
BzO
BzO
+
OH
OH
23
24
g
f
d
e
Cl
I
BzO
BzO
BzO
BzO
OAc
Cl
Cl
I
OMe
25
26
BzO
OBz BzO
OBz
R
R
I
R
I
a
b
N
N
N
27
28
Cl
N
Cl
I
N
MeO
N
Scheme 4 Reagents and conditions: a) BzCl, pyridine, 78%; b)
MCPBA, CH2Cl2, 77%; c) i.TMSOTf, DBU, toluene, ii. aq HCl,
MeOH, 34% of 23, 31% of 24; d) Ac2O, DMAP, MeCN, 92%;
e) NCS, PPh3, THF, 87%; f) NCS, PPh3, THF, 88%; g) NaI, TMSCl,
H2O, MeCN, 98%.
29 R = H
30 R = Me
31 R = H
32 R = Me
33 R = H
34 R = Me
OMe
N
I
N
35
OMe
Thus, substrate 25 was prepared by simple acetylation of
alcohol 23 with acetic anhydride in the presence of
DMAP as a catalyst. Both alcohols were converted to ap-
propriate allyl chlorides 26 and 27 on treatment with in
situ prepared complex triphenylphosphine–N-chlorosuc-
Scheme 5 Reagents and conditions: a) 57% HI; b) NaOMe, MeOH,
THF, 50% for 33 (two steps, 11% of byproduct 35), 56% for 34 (two
steps).
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4122
R. Nencka et al.
PAPER
and dried in dessicator over P2O5, because any other han- Unfortunately, regardless of the catalyst used, allyl ace-
dling (such as co-evaporation with a solvent), resulted in tate gave no reaction at all and reaction with allyl chlo-
rapid darkening and decomposition of the product. Fur- rides afforded only degradation products. The application
ther reaction of triiodopyrimidines with sodium methox- of lithium–tin exchange was unsuccessful as well. This
ide afforded the desired protected iodo derivatives. The behavior is surprising since similar reactions with either
usual by-product of this transformation was the alterna- organozinc species or stannanes are routinely performed
tive regioisomer 35. As shown in Table 2, all attempts to and were studied in detail.15 The results did not suggest
metalate the pyrimidine derivative and use the metalated whether the weak point is the lithiation procedure or the
species for cross-coupling reactions with allylic substrates cross-coupling reaction. Although the same lithiated pyri-
started with the preparation of organozinc intermediate by midine was successively used in a different synthesis,16
iodine–lithium exchange followed by transmetalation of fast darkening of the freshly lithiated intermediate indi-
lithium with zinc chloride. The organozinc species pre- cates rapid decomposition of this species. Therefore, we
pared was reacted under palladium catalysis with allyl decided to switch to the preparation of Grignard reagent
acetate 25 as well as with allyl chloride 26.
of this pyrimidine derivative according to the well estab-
Table 2 Cross-Coupling Reactions with Allyl Acetates and Chlorides
X
OMe
OMe
OMe
BzO
BzO
BzO
N
N
N
BzO
conditions b
conditions a
N
OMe
MeO
N
I
MeO
N
M
33
36
37
Entry
1
X
Conditions a
M
Conditions b
5 mol% Pd(PPh3)4, 60 °C
Solvent
THF
Yield (%)
nra
OAc
1. BuLi, –78 °C
2. ZnCl2, r.t.
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
ZnCl
Bu3Sn
ZnCl
2
3
4
5
6
7
8
9
OAc
OAc
OAc
OAc
Cl
1. BuLi, –78 °C
2. ZnCl2, r.t.
3 mol% Pd(AcO)2, 6 mol% DPEPhos, 60 °C
3 mol% Pd(AcO)2, 6 mol% XantPhos, 60 °C
3 mol% Pd(AcO)2, 6 mol% dppp, 60 °C
5 mol% Pd(dppf)2Cl2, 60 °C
THF
THF
THF
THF
THF
THF
THF
Et2O
nra
1. BuLi, –78 °C
2. ZnCl2, r.t.
nra
1. BuLi, –78 °C
2. ZnCl2 r.t.
nra
1. BuLi, –78 °C
2. ZnCl2, r.t.
nra
1. BuLi, –78 °C
2. ZnCl2, r.t.
5 mol% Pd(PPh3)4, 60 °C
dec.b
dec.b
dec.b
dec.b
Cl
1. BuLi, –78 °C
2. ZnCl2, r.t.
5 mol% Pd(dppf)2Cl2, 60 °C
Cl
1. BuLi, –78 °C
2. Bu3SnCl, r.t.
5 mol% Pd(dppf)2Cl2, 60 °C
Cl
1. BuLi, –78 °C
2. ZnCl2, r.t.
5 mol% Pd(PPh3)4, 60 °C
10
11
12
13
14
Cl
Cl
Cl
Cl
Cl
i-PrMgCl·LiCl, –25 °C
i-PrMgCl·LiCl, –25 °C
i-PrMgCl·LiCl, –25 °C
i-PrMgCl·LiCl, –25 °C
i-PrMgCl·LiCl, –25 °C
MgCl·LiCl
MgCl·LiCl
MgCl·LiCl
MgCl·LiCl
MgCl·LiCl
Pd2(dba)3, XPhos, –25 to 0 °C, 16 h, r.t.
5 mol% Pd(dppf)2Cl2, –25 to 0 °C, 16 h, r.t.
CuI·2LiCl, –25 to 0 °C, 16 h, 0 °C
Ni(dppp)2Cl2, –25 to 0 °C, 16 h, r.t.
CuI·2LiCl, –25 °C, 36 h
THF
THF
THF
THF
THF
trace
trace
26
8
77
a The starting allylic substrate remained unchanged; nr = no reaction.
b The starting allylic substrate decomposed.
Synthesis 2010, No. 23, 4119–4130 © Thieme Stuttgart · New York

PAPER
Convergent Approaches to Carbocyclic C-Nucleosides
4123
lished Knochel’s procedure17 using the reaction of pyrim- treatment with concentrated hydrochloric acid in a mix-
idinyl iodide with i-PrMgCl·LiCl.
ture of tetrahydrofuran and 1,4-dioxane. Furthermore, the
similar reaction scheme was also used for the preparation
of thymine derivatives 46 and 53 starting from pyrimidine
derivative 34 and allyl chlorides 26 and 27 (Scheme 7 and
Scheme 8).
Further screening of catalytic systems revealed that the
only acceptable results could be obtained under copper ca-
talysis. Although the screening attempt resulted in only
26% yield of the desired product, further optimization of
the reaction conditions led to the significant increase of
the reaction yield to 77%. Similar conditions were applied
also for the coupling of the magnesiated pyrimidine with
allyl chloride 27 and allyl iodide 28 (Table 3). The results
of the coupling reactions of both substrates are compara-
ble, because the yield of the reaction with allyl iodide in-
cludes also the previous step. However, as we stressed
above, the use of the iodide 28 should be avoided due to
its stability parameters. The only isolated product was the
isomer 38. The steric hinderance most likely prohibits the
allylic rearrangement and formation of isomeric product
often observed in this type of reactions under copper ca-
talysis.18
MeO
N
R1
OMe
OMe
N
R1
I
a
N
BzO
BzO
MeO
N
33 R1 = H
37 R1 = H
34 R1 = Me
40 R1 = Me
b
MeO
R1
O
N
N
NH
NH
OMe
R
O
Unfortunately, the product 38 exerted surprising sensitiv-
ity towards oxidative degradation and almost completely
decomposed in one month (Scheme 6). The main product
(~50%) of this degradation was identified as [4-(2,6-di-
methoxypyrimidin-4-yl)-2-oxocyclohex-3-ene-1,1-diyl]di-
methanediyl dibenzoate (39).
R2O
R2O
d
HO
HO
45 R = H
46 R = Me
41 R1 = H, R2 = Bz
42 R1 = Me, R2 = Bz
43 R1 = H, R2 = H
44 R1 = Me, R2 = H
c
c
OMe
N
OMe
N
BzO
BzO
BzO
BzO
a
Scheme 7 Reagents and conditions: a) i. i-PrMgCl·LiCl, THF,
–25 °C; ii. 26, CuI·2LiCl, THF, –25 °C, 77% for 37, 71% for 40; b)
H2, Pd(OH)2, MeOH, 95% for 41, 93% for 42; c) K2CO3, MeOH, 92%
for 43, 89% for 44; d) HCl, THF, 1,4-dioxane, 66% for 45, 72% for
46.
N
N
OMe
O
OMe
38
39
Scheme 6 Reagents and conditions: a) air, light, 1 month.
The crucial disadvantage of linear strategies towards new
carbocyclic C-nucleosides is low efficiency of single
steps leading to the diminished productivity of the whole
process. Herein, we have introduced two novel conver-
gent approaches for suitable synthesis of this class of nu-
cleoside analogues based on the application of
organometallic derivatives of 2,4-dimethoxypyrimidines.
The compounds 37 and 38 were therefore hydrogenated
right after their preparation to avoid this decomposition
process. Benzoyl groups were then removed by treatment
with potassium carbonate in methanol and the final prod-
ucts were released from their methylated precursors on
Table 3 Cross-Coupling Reactions with Allyl Chlorides and Iodides
X
OMe
OMe
OMe
BzO
BzO
conditions b
BzO
BzO
N
N
N
OMe
conditions a
N
MeO
N
33
X
I
I
MeO
N
M
36
M
38
Entry
1
Conditions a
Conditions b
Solvent
THF
Yield (%)
33
i-PrMgCl·LiCl,
–25 °C
MgCl·LiCl
MgCl·LiCl
MgCl·LiCl
CuI·2LiCl; –25 °C, 1 h; 0 °C, 4 h; 12 h, r.t.
CuI·2LiCl; –25 °C, 1 h; 0 °C, 4 h; 12 h, r.t.
CuI·2LiCl; –25 °C, 36 h
2
3
Cl
Cl
i-PrMgCl·LiCl,
–25 °C
THF
THF
41
60
i-PrMgCl·LiCl,
–25 °C
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4124
R. Nencka et al.
PAPER
electrospray ionization (ESI). The GC-MS analyses were per-
formed on an Agilent 5975B MSD. Preparative HPLC separations
were performed on a column packed with 10 mm C18 reversed-
phase silica gel (Luna), 250 × 21 mm; in ca 300 mg portions of mix-
tures using linear gradient 0.1 M triethylammonium hydrogen car-
bonate (TEAB) in H2O and in 50% MeOH (linear gradient of TEAB
in 50% MeOH, 0–100%). IR specra were recorded on an FTIR
Bruker Equinox IFS 55 spectrophotometer in KBr pellets or in
CHCl3. The elemental analyses were determined on a Perkin-Elmer
CHN Analyzer 2400, Series II Sys (Perkin Elmer, Norwolk, CT,
USA). Petroleum ether (PE) refers to the fraction boiling in the
range 50–70 °C.
One approach utilized the reaction of (4-chloro-2,6-
dimethoxypyrimidin-5-yl)lithium with the proper ketone
precursor as the essential step of the pseudouridine ana-
logue synthesis. The second approach employed copper-
catalyzed reaction of organomagnesium derivative of 2,4-
dimethoxypyrimidine with suitable allyl chloride in order
to prepare the derivatives with the carbocyclic ring con-
nected to the pyrimidine base at position C-6. These two
approaches open the desired direct way towards the car-
bocyclic C-nucleosides with the pseudosugar moiety
bonded to the uracil heterobase at the both possible posi-
tions (C-5 and C-6).
1-(4-Chloro-2,6-dimethoxypyrimidin-5-yl)-3,3-Bis(trityloxy-
methyl)cyclohexanol (10)
OMe
n-BuLi (1.6 M, 4.2 mL, 6.7 mmol) was added dropwise to a stirred
solution of 6-chloro-2,4-dimethoxypyrimidine (1.06 g, 6.06 mmol)
in THF (40 mL) cooled to –75 °C. After 25 min, a solution of ketone
6 (3 g, 4.66 mmol) in THF (35 mL) was added and the mixture was
stirred for 35 min at –75 °C, 2 h at –30 °C, and 16 h at 0 °C. The
resulting solution was partitioned between Et2O (2 × 300 mL) and
aq NH4Cl (200 mL) and the combined organic layers were washed
with brine (200 mL), dried (Na2SO4), evaporated, and the product
was purified by chromatography (PE–EtOAc, 4:1). Crystallization
from cyclohexane gave white crystals; yield: 3.14 g (82%); mp
196–197.5 °C.
R1
OMe
N
R1
I
BzO
BzO
a
N
N
MeO
N
OMe
33 R1 = H
38 R1 = H
34 R1 = Me
47 R1 = Me
b
MeO
R1
O
N
N
NH
NH
IR (CHCl3): 3572, 3088, 3062, 3034, 1595, 1568, 1541, 1490, 1484,
1449, 1389, 1318, 1184, 1160, 1153, 1102, 1075, 1069, 1032, 1002,
948, 899, 708, 700, 647, 633, 617, 534 cm–1.
R1
OMe
O
R2O
R2O
d
HO
HO
1H NMR (600.13 MHz, CDCl3): d = 1.26–1.37 (m, 3 H, H-4a, H-5),
1.64 (m, 2 H, H-6a and H-4b), 2.02 (dt, J = 14.7, 1.9 Hz, 1 H, H-2a),
2.08 (d, J = 14.7 Hz, 1 H, H-2b), 2.36 (m, 1 H, H-6b), 2.95 (d,
J = 8.4 Hz, 1 H, OCH2), 3.00 (d, J = 2.0 Hz, 1 H, OH), 3.37 (d,
J = 8.4 Hz, 1 H, OCH2), 3.49 (d, J = 8.8 Hz, 1 H, OCH2), 3.52 (d,
J = 8.8 Hz, 1 H, OCH2), 3.88 (s, 3 H, 4¢-OCH3), 3.95 (s, 3 H, 2¢-
OCH3), 7.19–7.27 (m, 18 H, C6H5), 7.33 (m, 6 H, C6H5), 7.45 (m, 6
H, C6H5).
52 R1 = H
48 R1 = H, R2 = Bz
53 R1 = Me
49 R1 = Me, R2 = Bz
50 R1 = H, R2 = H
51 R1 = Me, R2 = H
c
c
Scheme 8 Reagents and conditions: a) i. i-PrMgCl·LiCl, THF,
–25 °C; ii. 27, CuI·2LiCl, THF, –25 °C, 60% for 38, 52% for 47; b)
H2, Pd(OH)2, MeOH, 89% for 48, 80% for 49; c) K2CO3, MeOH; 85%
for 50, 66% for 51; d) HCl, THF, 1,4-dioxane, 75% for 52, 79% for
53.
13C NMR (150.92 MHz, CDCl3): d = 17.1, 29.2, 35.6, 38.9, 39.8,
54.9, 55.0, 63.8, 70.0, 74.5, 85.9, 86.1, 118.6, 126.6, 126.7, 127.5,
127.6, 128.7, 128.8, 144.1, 157.3, 161.1, 169.7.
HRMS-FAB: m/z [M + H]+ calcd for C52H49CIN2O5: 817.34083;
found: 817.34173.
Moreover, the latter method is not limited only to the
uracil derivatives but can be also used for the straightfor-
ward synthesis of thymine analogues. Although the pre-
liminary biological results of the synthesized nucleoside
derivatives hold little hope for further development of the
six-membered analogues, we are convinced that the ap-
plied procedures can be utilized in the synthesis of various
other interesting targets among carbocyclic C-nucleo-
sides.
5-[5,5-Bis(hydroxymethyl)cyclohex-1-enyl]-6-chloropyrimi-
dine-2,4(1H,3H)-dione (11) and 5-[3,3-Bis(hydroxymethyl)cy-
clohex-1-enyl]-6-chloropyrimidine-2,4(1H,3H)-dione (12)
A mixture of the substrate 10 (1.3 g, 1.59 mmol), concd HCl (5.3
mL), THF (6.5 mL), and 1,4-dioxane (7.8 mL) was heated to reflux
for 2.5 h. The resulting slurry was evaporated to a minimum volume
and partitioned between H2O (100 mL) and PE–toluene (1:5, 40
mL) and the organic phase was once washed with H2O (100 mL).
The combined aqueous portions were evaporated and the residue
was either purified by column chromatography (EtOAc–acetone–
EtOH–H2O, 20:3:1:1) to afford a mixture of products 11 and 12
(60%) used in the preparation of 13 or crystallized from H2O to give
the product 11 (156 mg, 34%). The mother liquor was then evapo-
rated and submitted to preparative HPLC, which gave 11 (101 mg,
22%) and 12 (49 mg, 11%).
The chemicals were obtained from commercial sources (Sigma-
Aldrich) or prepared according to published procedures. 4-Chloro-
2,6-dimethoxypyrimidine was sublimed under reduced pressure
(75 °C, ~ 1 mbar) before use. Melting points are uncorrected and
were determined on a Kofler block or on a Büchi Melting Point B-
540 apparatus. NMR spectra were recorded on Bruker Avance II
600 (1H NMR at 600 MHz, 13C NMR at 151 MHz), Bruker Avance
500 (1H NMR at 500 MHz, 13C NMR at 125.8 MHz) and Bruker
Avance 400 (1H NMR at 400 MHz, 13C NMR at 100.6 MHz) spec-
trometers. Mass spectra were measured on a ZAB-EQ (VG Analyt-
ical) spectrometer using FAB (ionization by Xe, accelerating
voltage 8 kV, glycerol matrix) or EI (electron energy 70 eV) or on
LTQ Orbitrap XL (Thermo Fisher Scientific) spectrometer using
11
White crystals; mp 247–248.5 °C (H2O).
IR (KBr): 3400, 3240, 3180, 3068, 3021, 1725, 1653, 1615, 1521,
1429, 1047, 1038, 1030 cm–1.
1H NMR (499.95 MHz, DMSO-d6): d = 1.39 (t, J = 6.5 Hz, 2 H, H-
4¢), 1.77 (m, 2 H, H-6¢), 2.07 (m, 2 H, H-3¢), 3.23 (dd, J = 10.6, 5.2
Synthesis 2010, No. 23, 4119–4130 © Thieme Stuttgart · New York

PAPER
Convergent Approaches to Carbocyclic C-Nucleosides
4125
Hz, 2 H, OCH2), 3.33 (dd, J = 10.6, 5.7 Hz, 2 H, OCH2), 4.32 (t,
J = 5.5 Hz, 2 H, OH), 5.53 (m, 1 H, H-2¢), 11.27 (br s, 1 H, NH)
11.86 (br s, 1 H, NH).
13C NMR (125.73 MHz, DMSO-d6): d = 22.0, 24.1, 32.5, 38.6,
64.4, 114.00, 128.5, 128.8, 141.3, 149.9, 162.4.
HRMS-ESI: m/z [M + Na]+ calcd for C12H15ClN2O4 + Na:
309.0613; found: 309.0612.
1H NMR (499.95 MHz, DMSO-d6): d = 1.13 (dt, J = 13.5, 4.1 Hz,
2 H, H-3¢ax and H-5¢ax), 1.36 (m, 2 H, H-2¢ax and H-6¢ax), 1.47 (dm,
J = 13.2 Hz, 2 H, H-2¢eq and H-6¢eq), 1.53 (dm, 2 H, H-3¢eq and H-
5¢eq), 2.25 (tt, J = 12.1, 3.2 Hz, 1 H, H-1¢), 3.16 (d, J = 5.5 Hz, 2 H,
CH2O), 3.40 (dd, J = 5.4 Hz, 2 H, CH2O), 4.22 (t, J = 5.4 Hz, 1 H,
OH), 4.30 (t, J = 5.5 Hz, OH), 1 H, OH), 7.07 (s, 1 H, H-6), 10.61
(br s, 1 H, NH), 10.95 (br s, 1 H, NH).
13C NMR (125.73 MHz, DMSO-d6): d = 26.7, 29.2, 35.1, 38.5,
61.1, 68.7, 117.3, 136.5, 151.3, 164.4.
HRMS-ESI: m/z [M + Na]+ calcd for C12H18N2O4 + Na: 277.11588;
Anal. Calcd for C12H15ClN2O4: C, 50.27; H, 5.27; N, 9.77. Found:
C, 50.06; H, 5.18; N, 9.52.
found: 277.11585.
12
White crystals; mp 233 °C (H2O).
1-(2,4-Dimethoxypyrimidin-5-yl)-3,3-bis(trityloxymethyl)cy-
clohexanol (14) and 1-(2,4-Dimethoxypyrimidin-5-yl)-4,4-
bis(trityloxymethyl)cyclohexanol (19)
IR (KBr): 3433, 3223, 3169, 3046, 1721, 1673, 1613, 1511, 1487,
1429, 1040, 1029 cm–1.
1H NMR (600.13 MHz, DMSO-d6): d = 1.34 (m, 2 H, H-4¢), 1.58
(m, 2 H, H-5¢), 1.98 (dt, J = 6.2, 1.6 Hz, 2 H, H-6¢), 3.24 (dd,
J = 10.4, 5.3 Hz, 2 H, CH2Oa), 3.31 (dd, J = 10.4, 5.1 Hz, 2 H,
CH2Ob), 4.41 (t, J = 5.5 Hz, 2 H, OH), 5.43 (t, J = 1.8 Hz, 1 H, H-
2¢), 11.27 (br s, 1 H, NH), 11.86 (br s, 1 H, NH).
13C NMR (150.92 MHz, DMSO-d6): d = 18.8, 25.8, 28.2, 42.2,
64.4, 113.9, 131.1, 133.2, 141.4, 149.9, 162.3.
The starting chloro derivative 10 or 16 (1 g, 3.8 mmol) was mixed
with toluene (17 mL), abs. EtOH (23 mL), and Et3N (329 mg).
Pd(OH)2 on activated carbon (145 mg) was added and the suspen-
sion was kept under H2 atmosphere for 16 h. Filtration through a
Celite pad followed by evaporation and chromatography on silica
gel (toluene–EtOAc, 4:1) afforded the products 10 (94%) and 16
(98%) as white foams.
HRMS-ESI: m/z [M + Na]+ calcd for C12H15ClN2O4 + Na:
309.06126; found: 309.06131.
14
IR (CHCl3): 3572, 3088, 3062, 3034, 1595, 1568, 1541, 1490, 1484,
1449, 1389, 1318, 1184, 1160, 1153, 1102, 1075, 1069, 1032, 1002,
948, 899, 708, 700, 647, 633, 617, 534 cm–1.
Anal. Calcd for C12H15ClN2O4: C, 50.27; H, 5.27; N, 9.77. Found:
C, 50.01; H, 5.24; N, 9.43.
1H NMR (499.95 MHz, DMSO-d6): d = 0.92 (m, 1 H, H-4a), 1.07–
1.20 (m, 3 H, H-6a and H-5), 1.38 (d, J = 14.3 Hz, 1 H, H-2a), 1.69
(dm, J = 13.0 Hz, 1 H, H-4b), 1.87 (m, 1 H, H-6b), 2.04 (d, J = 14.6
Hz, 1 H, H-2b), 2.74 (d, J = 8.2 Hz, 1 H, OCH2), 3.25 (d, J = 9.2 Hz,
1 H, OCH2), 3.36 (d, J = 8.3 Hz, 1 H, OCH2), 3.80 (d, J = 9.1 Hz, 1
H, OCH2), 3.84 (s, 6 H, OCH3), 4.56 (s, 1 H, OH), 7.22–7.34 (m, 30
H, 3 × C6H5), 8.20 (s, 1 H, H-6¢).
13C NMR (125.73 MHz, DMSO-d6): d = 16.5, 27.9, 35.0, 39.4,
41.0, 53.9, 54.5, 63.2, 69.6, 70.6, 85.5, 85.7, 122.6, 126.9, 127.1,
127.9, 128.6, 144.2, 144.5, 156.2, 164.0, 167.2.
5-[3,3-Bis(hydroxymethyl)cyclohexyl]pyrimidine-2,4(1H,3H)-
dione (13) and 5-[4,4-Bis(hydroxymethyl)cyclohexyl]pyrimi-
dine-2,4(1H,3H)-dione (18); General Procedure
Pd(OH)2/C (70 mg) was added to a solution of the substrate (1
mmol) in MeOH (10 mL) and the mixture was stirred under H2 at-
mosphere for 48 h. The catalyst was removed by filtration through
a Celite pad, washed thoroughly with hot MeOH, and the filtrate
was evaporated. Chromatography on a short column of silica gel
(EtOAc–acetone–EtOH–H2O, 36:6:5:3) and crystallization from aq
EtOH afforded the products 13 and 18, respectively.
HRMS-FAB: m/z [M + H]+ calcd for C52H50N2O5: 783.37980;
found: 783.38280.
13
Prepared from a mixture of 11 and 12; yield: 87%; pale gray crys-
tals; mp 292–293.5 °C.
19
FT-IR (CHCl3): 3576, 3088, 3062, 3034, 1596, 1567, 1490, 1476,
1449, 1386, 1319, 1186, 1160, 1153, 1112, 1090, 1074, 1033, 964,
900, 803, 707, 700, 644, 633, 617, 539 cm–1.
1H NMR (600.13 MHz, DMSO-d6): d = 1.19 (dm, J = 13.8 Hz, 2 H,
H-3eq and H-5eq), 1.43 (td, J = 13.6, 4.3 Hz, 2 H, H-2ax and H-6ax),
1.55 (dm, J = 13.4 Hz, 2 H, H-2eq and H-6eq), 1.97 (td, J = 13.8, 4.2
Hz, 2 H, H-3ax and H-5ax), 3.03 (s, 2 H, OCH2), 3.31 (s, 2 H, OCH2),
3.35 (s, 3 H, 4¢-OCH3), 3.83 (s, 3 H, 2¢-OCH3), 7.19–7.39 (m, 30 H,
3 × C6H5), 8.25 (s, 1 H, H-6¢).
13C NMR (150.92 MHz, DMSO-d6): d = 26.1, 30.0, 37.8, 53.6,
54.5, 62.2, 68.9, 70.0, 85.6, 85.8, 122.5, 127.0, 127.2, 127.9, 128.1,
128.6, 128.6, 144.2, 144.3, 155.8, 164.0, 167.4.
HRMS-FAB: m/z [M + H]+ calcd for C52H50N2O5: 783.37980;
found: 783.38238.
IR (KBr): 3297, 3230, 3170, 3130, 3082, 3031, 1711, 1672, 1480,
1431, 1234, 1199, 1055, 1049, 774 cm–1.
1H NMR (499.95 MHz, DMSO-d6): d = 0.97–1.05 (m, 2 H, H-4¢ax
and H-6¢ax), 1.09 (t, J = 13.0 Hz, 1 H, H-2¢ax), 1.35–1.54 (m, 4 H, H-
2¢eq, H-4¢eq and H-5¢), 1.70 (dm, J = 13.0 Hz, 1 H, H-6¢eq), 2.50 (m,
1 H, H-1¢), 3.13 (dd, J = 10.4, 5.7 Hz, 1 H, CH2O), 3.18 (dd,
J = 10.4, 5.6 Hz, 1 H, CH2O), 3.40 (m, 2 H, CH2O), 4.26 (t, J = 5.3
Hz, 1 H, OH), 4.30 (t, J = 5.6 Hz, 1 H, OH), 7.01 (s, 1 H, H-6), 10.61
(br s, 1 H, NH), 10.96 (br s, 1 H, NH).
13C NMR (125.73 MHz, DMSO-d6): d = 21.6, 28.3, 29.5, 32.1,
34.4, 39.9, 61.3, 68.7, 117.6, 136.4, 151.2, 164.4.
HRMS-ESI: m/z [M + Na]+ calcd for C12H18N2O4 + Na: 277.11588;
found: 277.11586.
Anal. Calcd for C12H18N2O4·H2O: C, 55.69; H, 7.21; N, 10.82.
Found: C, 54.65; H, 7.20; N, 10.54.
1-(4-Chloro-2,6-dimethoxypyrimidin-5-yl)-4,4-bis(trityloxy-
methyl)cyclohexanol (16)
18
n-BuLi (1.6 M in hexanes, 4.2 mL, 6.7 mmol) was added dropwise
to a stirred solution of 6-chloro-2,4-dimethoxypyrimidine (8; 1.06
g, 6.06 mmol) in THF (40 mL) cooled to –75 °C. After 30 min, the
solution of ketone 7 (3 g, 4.66 mmol) in THF (35 mL) was added
and the mixture was stirred for 35 min at –75 °C, 4 h at –30 °C, and
16 h at –10 °C. The resulting solution was partitioned between Et2O
Prepared from 17 (see below); yield: 89%; pale gray crystals; mp
329.5–330 °C.
IR (KBr): 3332, 3280, 3219, 3078, 3045, 1712, 1666, 1497, 1435,
1241, 1208, 1043, 775 cm–1.
Synthesis 2010, No. 23, 4119–4130 © Thieme Stuttgart · New York

4126
R. Nencka et al.
PAPER
(2 × 300 mL) and aq NH4Cl (200 mL) and the combined organic
portions were washed with brine (200 mL), dried (Na2SO4), evapo-
rated and the product was purified by chromatography (PE–EtOAc,
4:1) and crystallization from EtOH to give 16 as white crystals;
yield: 3.4 g (89%); mp 131 °C (hydrate) and 165 °C (anhyd).
HRMS-ESI: m/z [M + Na]+ calcd for C12H15ClN2O4 + Na:
309.06126; found: 309.06101.
Anal. Calcd for C12H15ClN2O4·1/2H2O: C, 48.74; H, 5.45; N, 9.47.
Found: C, 48.60; H, 5.46; N, 9.36.
IR (CHCl3): 3571, 3088, 3062, 3034, 1597, 1570, 1541, 1490, 1483,
1449, 1389, 1316, 1183, 1160, 1153, 1103, 1082, 1071, 1031, 948,
900, 707, 700, 644, 633, 617, 539, 469 cm–1.
5-[4,4-Bis(hydroxymethyl)cyclohex-1-enyl]pyrimidine-
2,4(1H,3H)-dione (20)
Prepared from 19; yield: 49%; pale gray crystals; mp >340 °C
(H2O–MeOH).
1H NMR (600.13 MHz, DMSO-d6): d = 1.45 (m, 6 H, H-2, H-6, H-
3a, and H-5a), 1.96 (m, 2 H, H-3b and H-5b), 3.03 (s, 2 H OCH2),
3.31 (s, 2 H, OCH2), 3.45 (s, 3 H, 4¢-OCH3), 3.83 (s, 3 H, 2¢-OCH3),
4.59 (s, 1 H, OH), 7.21–7.36 (m, 30 H, 3 × C6H5).
13C NMR (150.92 MHz, DMSO-d6): d = 26.1, 30.1, 37.6, 54.6,
55.0, 62.1, 69.1, 72.1, 85.6, 85.8, 127.1, 127.1, 127.9, 128.1, 128.6,
144.2, 144.3, 158.0, 161.1, 169.3.
IR (KBr): 3330, 3210, 3086, 3055, 1722, 1666, 1619, 1488, 1430,
1246, 1219, 1042, 1032, 829, 784 cm–1.
1H NMR (499.95 MHz, DMSO-d6): d = 1.45 (t, J = 6.5 Hz, 2 H, H-
5¢), 1.85 (m, 2 H, H-3¢), 2.13 (m, 2 H, H-6¢), 3.23 (dd, J = 10.5, 5.3
Hz, 2 H, CH2Oa), 3.27 (dd, J = 10.5, 5.4 Hz, 2 H, CH2Ob), 4.34 (t,
J = 5.4 Hz, 2 H, OH), 6.19 (m, 1 H, H-2¢), 7.17 (s, 1 H, H-6), 10.79
(br s, 1 H, NH), 10.99 (br s, 1 H, NH).
13C NMR (125.73 MHz, DMSO): d = 23.4, 25.5, 29.7, 37.5, 64.5,
113.9, 124.5, 129.4, 137.1, 150.9, 163.5.
HRMS–FAB: m/z [M + H]+ calcd for C52H49CIN2O5: 817.34083;
found: 817.34296.
Deprotection/Elimination Procedure; Preparation of Deriva-
tives 15, 17, and 20; General Procedure
HRMS-ESI: m/z [M + Na]+ calcd for C12H16N2O4 + Na: 275.10023;
found: 275.10030.
A mixture of substrate (1.22 mmol), concd HCl (4.1 mL), THF (4
mL), 1,4-dioxane (6 mL), and H2O (0.7 mL) was heated to reflux
for 2 h. The resulting slurry was evaporated to a minimum volume
and partitioned between H2O (70 mL) and PE–toluene (1:5, 30 mL).
The organic phase was once extracted with H2O (70 mL). The com-
bined aqueous portions were evaporated and the residue was puri-
fied by crystallization to give the products.
Anal. Calcd for C12H16N2O4·H2O: C, 56.13; H, 6.48; N, 10.91.
Found: C, 56.15; H, 6.47; N, 10.56.
Coupling of Iodopyrimidines 33 and 34 with Allyl Chlorides 26
and 27; General Procedure
A solution of i-PrMgCl·LiCl in THF (1 M, 4.3 mL) was added to a
solution of iodopyrimidine 33 or 34 (3.9 mmol) in THF (14 mL) un-
der an argon atmosphere at –25 °C. The reaction mixture was stirred
under the same conditions for 1 h before a solution of allyl chloride
26 (2.6 mmol) in THF (27 mL), treated with a solution of CuI (95
mg, 0.5 mmol) and LiCl (42 mg, 1 mmol) in THF (0.84 mL), was
added via a syringe. The resulting mixture was stirred at –25 °C for
48 h. Sat. aq NH4Cl (100 mL) was added to the reaction mixture fol-
lowed by 5% aq NH4OH (15 mL) and sat. aq Na2EDTA (15 mL).
The biphasic system was extracted with Et2O (3 × 150 mL). The
combined organic layers were washed with H2O (100 mL), dried
(Na2SO4), and evaporated. Chromatography on a silica gel column
afforded the products.
trans-5-[1-(Hydroxymethyl)-6-oxabicyclo[3.2.1]octan-5-yl]py-
rimidine-2,4(1H,3H)-dione (15)
This compound was prepared from 14 according to the general pro-
cedure, but the crystallization was preceded by a column chroma-
tography (EtOAc–acetone–EtOH– H2O, 20:3:1:1); yield: 58%;
white crystals; mp 264 °C (H2O).
IR (KBr): 3303, 3237, 3170, 3116, 3032, 1710, 1661, 1496, 1428,
1229, 1203, 1059, 1047, 1035, 763 cm–1.
1H NMR (600.13 MHz, DMSO-d6): d = 1.29–1.36 (m, 2 H, H-4¢ax
and H-6¢eq), 1.52 (dt, J = 11.1, 2.3 Hz, 1 H, H-2¢eq), 1.57 (m, 1 H, H-
4¢eq), 1.62–1.71 (m, 2 H, H-5¢), 1.97 (d, J = 11.1 Hz, 1 H, H-2¢ax),
2.05 (m, 1 H, H-6¢ax), 3.27–3.40 (m, 2 H, CH2OH), 3.60 (dd, J = 7.5,
1.9 Hz, 1 H, CH2O), 3.70 (d, J = 7.5 Hz, 1 H, CH2O), 4.62 (t, J = 5.4
Hz, 1 H, OH), 7.20 (s, 1 H, H-6), 10.65 (br s, 1 H, NH), 11.01 (br s,
1 H, NH).
13C NMR (150.92 MHz, DMSO-d6): d = 19.5, 31.6, 35.9, 44.3,
47.1, 65.6, 74.0, 82.0, 117.5, 136.2, 151.4, 163.2.
HRMS-ESI: m/z [M + Na]+ calcd for C12H16N2O4 + Na: 275.10023;
found: 275.10027.
[5-(2,6-Dimethoxypyrimidin-4-yl)cyclohex-3-ene-1,1-diyl]bis-
methylene Dibenzoate (37)
Prepared from 26 and 33. Chromatography: hexanes–EtOAc (6:1);
yield: 77%; air-sensitive colorless oil.
1H NMR (499.95 MHz, CDCl3): d = 1.87 (dd, J = 13.3, 10.9 Hz, 1
H, H-6), 2.17–2.26 (m, 2 H, H-2), 2.28 (m, 1 H, H-6b), 3.51 (m, 1
H, H-5), 3.92 (s, 3 H, 2¢-OCH3), 3.93 (s, 3 H, 6¢-OCH3), 4.33 (m, 2
H CH2O), 4.47 (s, 2 H, CH2O), 5.85 (dm, J = 10.1 Hz, 1 H, H-4),
5.88 (dm, J = 10.1 Hz, 1 H, H-3), 6.26 (s, 1 H, H-5¢), 7.39–7.44 (m,
4 H, H-3¢¢), 7.53–7.58 (m, 2 H, H-4¢¢), 7.99 (m, 2 H, H-2¢¢), 8.04 (m,
2 H H-2¢¢).
Anal. Calcd for C12H16N2O4·H2O: C, 56.13; H, 6.48; N, 10.91.
Found: C, 56.09; H, 6.18; N, 10.74.
13C NMR (125.70 MHz, CDCl3): d = 29.8, 32.9, 37.2, 40.1, 53.8,
54.5, 65.3, 69.3, 96.6, 125.9, 127.3, 128.4, 128.4, 129.6, 129.6,
129.9, 130.0, 133.1, 133.1, 165.3, 166.3, 166.5, 172.2, 174.7.
5-[4,4-Bis(hydroxymethyl)cyclohex-1-enyl]-6-chloropyrimi-
dine-2,4(1H,3H)-dione (17)
Prepared from 16; yield: 70%; pale yellow crystals; mp 249–
HRMS-ESI: m/z [M + Na]+ calcd for C28H28N2O6 + Na: 511.1840;
250.5 °C (H2O).
found: 511.1836.
IR (KBr): 3314, 3225, 3152, 3052, 3030, 1735, 1661, 1611, 1518,
1479, 1430, 1035, 825 cm–1.
[5-(2,6-Dimethoxy-5-methylpyrimidin-4-yl)cyclohex-3-ene-1,1-
diyl]bismethylene Dibenzoate (40)
Prepared from 26 and 34. Chromatography: hexanes–EtOAc (5:1);
1H NMR (499.95 MHz, DMSO-d6): d = 1.46 (t, J = 6.0 Hz, 2 H, H-
5¢), 1.83 (m, 2 H, H-3¢), 1.99 (m, 2 H, H-6¢), 3.26 (dd, J = 10.5, 5.1
Hz, 2 H, CH2Oa), 3.32 (dd, J = 10.5, 5.3 Hz, 2 H, CH2Ob), 4.37 (t,
J = 5.4 Hz, 2 H, OH), 5.48 (m, 1 H, H-2¢), 11.30 (br s, 1 H, NH),
11.88 (br s, 1 H, NH).
13C NMR (125.73 MHz, DMSO-d6): d = 24.4, 25.3, 29.5, 37.6,
64.4, 113.9, 128.4, 129.2, 141.0, 149.9, 162.3.
yield: 71%; air-sensitive colorless oil.
1H NMR (499.95 MHz, CDCl3): d = 1.98 (dd, J = 13.2, 11.3 Hz, 1
H, H-6), 1.99 (s, 3 H, 5¢-CH3), 2.06 (m, 1 H, H-6b), 2.17 (dm, 1 H,
J = 18.2 Hz, H-2), 2.33 (dm, J = 18.2 Hz, 1 H, H-2), 3.81 (m, 1 H,
Synthesis 2010, No. 23, 4119–4130 © Thieme Stuttgart · New York

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Convergent Approaches to Carbocyclic C-Nucleosides
4127
H-5), 3.92 (s, 3 H, 2¢-OCH3), 3.94 (s, 3 H, 6¢-OCH3), 4.35 (d,
J = 11.0 Hz, 1 H, CH2O), 4.38 (d, J = 11.0 Hz, 1 H, CH2O), 4.44 (d,
J = 11.3 Hz, 1 H, CH2O), 4.60 (d, J = 11.3 Hz, 1 H, CH2O), 5.73
(dm, J = 10.1 Hz, 1 H, H-4), 5.83 (dm, J = 10.1 Hz, 1 H, H-3), 7.40–
7.45 (m, 4 H, H-3¢¢), 7.53–7.58 (m, 2 H, H-4¢¢), 8.00–8.05 (m, 4 H,
H-2¢¢).
13C NMR (125.70 MHz, CDCl3): d = 9.4, 29.8, 31.2, 36.3, 37.1,
53.9, 54.3, 65.1, 69.7, 107.4, 124.6, 127.9, 128.4, 128.4, 129.5,
129.8, 129.9, 133.0, 133.1, 163.0, 166.3, 166.5, 169.8, 170.0.
HRMS-ESI: m/z [M + Na]+ calcd for C28H26N2O7 + Na: 525.1632;
found: 525.1628.
Hydrogenation of the Coupling Products; General Procedure
Pd(OH)2/C (150 mg) was added to a solution of the substrate (1.5
mmol) in MeOH (75 mL) and the mixture was stirred under H2 at-
mosphere for 20 h. The catalyst was removed by filtration through
a Celite pad and the filtrate was evaporated. Products were purified
by column chromatography.
HRMS-ESI: m/z [M + H]+ calcd for C29H30N2O6: 503.21766; found:
503.21772.
[3-(2,6-Dimethoxypyrimidin-4-yl)cyclohexane-1,1-diyl]bis-
methylene Dibenzoate (41)
Prepared from 37. Chromatography: hexanes–EtOAc (5:1); yield:
95%; colorless oil.
[4-(2,6-Dimethoxypyrimidin-4-yl)cyclohex-2-ene-1,1-diyl]bis-
methylene Dibenzoate (38)
Prepared from 27 and 33. Chromatography: hexanes–EtOAc (4:1);
yield: 60%; air-sensitive colorless oil.
1H NMR (600.13 MHz, DMSO-d6): d = 1.72 (m, 1 H, H-6¢a), 1.89
(m, 2 H, H-5¢a and H-6¢b), 2.05 (m, 1 H, H-5¢b), 3.43 (m, 1 H, H-
4¢), 3.87 (s, 3 H, OCH3), 3.87 (s, 3 H, OCH3), 4.29 (d, J = 10.9 Hz,
1 H, OCH2), 4.32 (d, J = 11.0 Hz, 1 H, OCH2), 4.38 (d, J = 10.9 Hz,
1 H, OCH2), 4.42 (d, J = 11.0 Hz, 1 H, OCH2), 5.88 (dd, J = 10.2,
2.3 Hz, 1 H, H-2¢), 6.03 (dd, J = 10.2, 3.1 Hz, 1 H, H-3¢), 6.40 (s, 1
H, H-5), 7.51 (m, 4 H, H-3¢¢), 7.66 (m, 2 H, H-4¢¢), 7.95 (m, 2 H, H-
2¢¢), 7.99 (m, 2 H, H-2¢¢).
13C NMR (150.92 MHz, DMSO-d6): d = 24.2, 25.4, 39.2, 42.1,
53.9, 54.5, 67.3, 67.8, 99.0, 129.0, 129.1, 129.2, 129.4, 129.4,
129.6, 129.7, 131.8, 133.7, 133.7, 165.1, 165.8, 171.8, 174.6.
HRMS-ESI: m/z [M + Na]+ calcd for C28H28N2O6 + Na: 511.1840;
found: 511.1836.
IR (CHCl3): 3092, 3065, 3027, 1718, 1596, 1585, 1568, 1494, 1480,
1453, 1386, 1316, 1280, 1269, 1177, 1111, 1070, 1027, 985, 838,
713, 687, 617 cm–1.
1H NMR (600.13 MHz, CDCl3): d = 1.43 (td, J = 13.6, 4.4 Hz, 1 H,
H-6ax), 1.56 (m, 1 H, H-4ax), 1.67 (qt, J = 13.7, 3.6 Hz, 1 H, H-6ax),
1.68 (dd, J = 13.6, 12.9 Hz, 1 H, H-2ax), 1.82 (dm, J = 14.0 Hz, 1 H,
H-5eq), 1.92 (dm, J = 13.7 Hz, 1 H, H-6eq), 1.98 (dm, J = 12.7 Hz, 1
H, H-4eq), 2.06 (dm, J = 13.6 Hz, 1 H, H-2eq), 2.83 (m, 1 H, H-3),
3.93 (s, 3 H, 2¢-OCH3), 3.94 (s, 3 H, 6¢-OCH3), 4.27 (d, J = 10.9 Hz,
1 H, CH2O), 4.32 (d, J = 10.9 Hz, 1 H, CH2O), 4.58 (s, 2 H, CH2O),
6.21 (s, 1 H, H-5¢), 7.40–7.44 (m, 4 H, H-3¢¢), 7.53–7.57 (m, 2 H, H-
4¢¢), 8.01–8.04 (m, 4 H, H-2¢¢).
13C NMR (150.92 MHz, CDCl3): d = 21.0, 29.3, 31.2, 34.9, 38.2,
40.1, 53.7, 54.5, 64.0, 70.8, 98.4, 128.3, 128.4, 129.6, 129.6, 129.1,
130.0, 133.0, 133.1, 165.2, 166.4, 166.4, 172.0, 175.6.
HRMS-FAB: m/z [M + Na]+ calcd for C28H30N2O6 + Na:
513.19961; found: 513.19922.
[4-(2,6-Dimethoxy-5-methylpyrimidin-4-yl)cyclohex-2-ene-1,1-
diyl]bismethylene Dibenzoate (47)
Prepared from 27 and 34. Chromatography: hexanes–EtOAc (11:2);
[3-(2,6-Dimethoxy-5-methylpyrimidin-4-yl)cyclohexane-1,1-
diyl]bismethylene Dibenzoate (42)
Prepared from 40. Chromatography: hexanes–EtOAc (5:1); yield:
93%; colorless oil.
yield: 52%; air-sensitive colorless oil.
1H NMR (600.13 MHz, CDCl3): d = 1.75 (ddd, J = 13.6, 11.9 Hz,
3.6 Hz, 1 H, H-6a), 1.96 (m, 1 H, H-5a), 2.02 (m, 1 H, H-5b), 2.10
(s, 3 H, 5¢-CH3), 2.12 (m, 1 H, H-6b), 3.72 (m, 1 H, H-4), 4.33 (d,
J = 10.8 Hz, 1 H, CH2O), 4.40 (d, J = 11.1 Hz, 1 H, CH2O), 4.45 (d,
J = 10.8 Hz, 1 H, CH2O), 4.54 (d, J = 11.1 Hz, 1 H, CH2O), 5.85
(ddd, J = 10.2, 2.5, 1.1 Hz, 1 H, H-2), 5.93 (ddd, J = 10.2, 2.5, 0.8
Hz, 1 H, H-3), 7.41–7.46 (m, 4 H, H-3¢¢), 7.54–7.58 (m, 2 H, H-4¢¢),
8.02–8.06 (m, 4 H, H-2¢¢).
13C NMR (150.92 MHz, CDCl3): d = 9.6, 23.8, 26.7, 38.9, 39.6,
54.0, 54.4, 66.8, 68.3, 107.4, 127.6, 128.4, 128.4, 129.6, 130.0,
132.5, 133.0, 133.1, 162.9, 166.3, 166.4, 169.9, 169.9.
HRMS-ESI: m/z [M + H]+ calcd for C29H30N2O6: 503.21766; found:
503.21760.
IR (CHCl3): 3065, 3029, 3027, 1718, 1602, 1584, 1575, 1492, 1475,
1391, 1380, 1371, 1316, 1284, 1269, 1177, 1113, 1082, 1071, 1027,
1009, 978, 937, 713, 687, 617, 532 cm–1.
1H NMR (600.13 MHz, CDCl3): d = 1.50 (td, J = 13.5, 4.5 Hz, 1 H,
H-6ax), 1.68 (m, 1 H, H-4ax), 1.70–1.86 (m, 5 H, H-2, H-5 and H-
4eq), 1.92 (dm, J = 14.0 Hz, 1 H, H-6eq), 2.01 (s, 3 H, 5¢-CH3), 3.14
(m, 1 H, H-3), 3.94 (s, 3 H, 2¢-OCH3), 3.94 (s, 3 H, 6¢-OCH3), 4.28
(d, J = 10.9 Hz, 1 H, CH2O), 4.32 (d, J = 10.9 Hz, 1 H, CH2O), 4.54
(d, J = 11.4 Hz, 1 H, CH2O), 4.70 (d J = 11.4 Hz, 1 H, CH2O), 7.39–
7.43 (m, 4 H, H-3¢¢), 7.53–7.57 (m, 2 H, H-4¢¢), 8.01–8.04 (m, 4 H,
H-2¢¢).
13C NMR (150.92 MHz, DMSO-d6): d = 9.2, 21.1, 29.5, 30.4, 33.9,
35.5, 38.2, 53.9, 54.2, 64.0, 70.9, 106.8, 128.3, 128.4, 129.5, 129.5,
129.8, 130.0, 133.0, 133.1, 165.9, 166.3, 166.4, 169.7, 171.1.
HRMS-ESI: m/z [M + H]+ calcd for C29H32N2O6: 505.23331; found:
505.23339.
[4-(2,6-Dimethoxypyrimidin-4-yl)-2-oxocyclohex-3-ene-1,1-
diyl]bismethylene Dibenzoate (39)
The compound 38 (300 mg, 0.6 mmol) was exposed to sunlight in a
glass vessel for 1 month. The mixture of products was chromato-
graphed (hexanes–EtOAc, 3:1) on a silica gel column to afford the
product 39 (154 mg, 50%).
1H NMR (600.13 MHz, DMSO-d6): d = 2.39 (t, J = 6.3 Hz, 2 H, H-
6¢), 2.98 (td, J = 6.3, 1.7 Hz, 2 H, H-5¢), 3.94 (s, 3 H, 6-OCH3), 3.94
(s, 3 H, 2-OCH3), 4.59 (d, J = 11.3 Hz, 2 H, CH2O), 4.61 (d,
J = 11.3 Hz, 2 H, CH2O), 7.00 (s, 2 H, H-5 and H-3¢), 7.50 (m, 4 H,
H-3¢¢), 7.66 (m, 2 H, H-4¢¢), 7.93 (m, 4 H, H-2¢¢).
13C NMR (150.92 MHz, DMSO-d6): d = 22.3, 26.8, 48.2, 54.4,
54.8, 64.9, 99.7, 126.5, 129.1, 129.4, 129.4, 133.8, 155.3, 163.6,
164.9, 165.6, 172.7, 199.3.
[4-(2,6-Dimethoxypyrimidin-4-yl)cyclohexane-1,1-diyl]bis-
methylene Dibenzoate (48)
Prepared from 38. Chromatography: hexanes–EtOAc (4:1); yield:
89%; colorless oil.
IR (CHCl3): 3092, 3072, 3065, 1718, 1596, 1585, 1567, 1494, 1480,
1452, 1386, 1315, 1287, 1272, 1177, 1108, 1071, 1027, 964, 839,
712, 687, 618 cm–1.
1H NMR (600.13 MHz, CDCl3): d = 1.57 (td, J = 13.6, 4.1 Hz, 2 H,
H-2¢ax), 1.80 (dm, J = 3.2 Hz, 2 H, H-3¢ax), 1.92 (dm, J = 13.9 Hz, 2
H, H-3¢eq), 2.01 (dm, J = 14.1 Hz, 2 H, H-2¢eq), 2.58 (tt, J = 11.9, 3.7
Synthesis 2010, No. 23, 4119–4130 © Thieme Stuttgart · New York

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R. Nencka et al.
PAPER
Hz, 1 H, H-4¢), 3.95 (s, 3 H, 6¢-OCH3), 3.98 (s, 3 H, 2¢-OCH3), 4.30
(s, 2 H, CH2O), 4.54 (s, 2 H, CH2O), 6.24 (s, 1 H, H-5), 7.41–7.45
(m, 4 H, H-3¢¢), 7.54–7.58 (m, 2 H, H-4¢¢), 8.02–8.05 (m, 4 H, H-2¢¢).
13C NMR (150.92 MHz, DMSO-d6): d = 26.3, 29.6, 37.2, 44.9,
53.7, 54.6, 64.1, 70.5, 98.1, 128.4, 129.6, 130.0, 130.0, 133.1,
165.2, 166.4, 166.4, 172.0, 175.7.
1H NMR (600.13 MHz, CDCl3): d = 1.09 (m, 1 H, H-6ax), 1.30 (t,
J = 12.9 Hz, 1 H, H-2ax), 1.45–1.60 (m, 6 H, H-4, 5, 2eq and 6eq),
2.00 (s, 3 H, 5¢-CH3), 2.97 (m, 1 H, H-3), 3.16 (m, 2 H, CH2O), 3.43
(m, 2 H, CH2O), 3.84 (s, 3 H, 2¢-OCH3), 3.87 (s, 3 H, 4¢-OCH3), 4.35
(t, J = 5.3 Hz, 1 H, OH) 4.35 (t, J = 5.5 Hz, 1 H, OH).
13C NMR (150.92 MHz, DMSO): d = 9.2, 21.2, 28.6, 30.3, 34.0,
35.7, 39.6, 54.0, 54.1, 61.4, 68.7, 106.3, 162.7, 169.2, 172.7.
HRMS-FAB: m/z [M + Na]+ calcd for C28H30N2O6: 513.19961;
found: 513.19922.
HRMS-ESI: m/z [M + H]+ calcd for C15H24N2O4: 297.18088; found:
297.18096.
[4-(2,6-Dimethoxy-5-methylpyrimidin-4-yl)cyclohexane-1,1-
diyl]bismethylene Dibenzoate (49)
Prepared from 47. Chromatography: hexanes–EtOAc (5:1); yield:
Anal. Calcd for C15H24N2O4: C, 60.79; H, 8.16; N, 9.45. Found: C,
60.71; H, 8.33; N, 9.40.
80%; colorless oil.
[4-(2,6-Dimethoxypyrimidin-4-yl)cyclohexane-1,1-diyl]dimeth-
anol (50)
Prepared from 48. Chromatography: EtOAc–acetone–EtOH–H2O
(20:3:1:1); yield: 85%; white crystals; mp 123–123.5 °C (EtOAc–
toluene).
IR (CHCl3): 3092, 3072, 3065, 3027, 1718, 1602, 1585, 1491, 1476,
1453, 1391, 1381 1370, 1315, 1273, 1177, 1110, 1083, 1071, 1027,
1010, 960, 938, 713, 687, 617, 532 cm–1.
1H NMR (600.13 MHz, CDCl3): d = 1.55 (td, J = 13.6, 4.2 Hz, 2 H,
H-2¢, 6¢ax), 1.68 (dm, J = 13.9 Hz, 2 H, H-3¢, 5¢eq), 1.99 (m, 2 H, H-
3¢, 5¢ax), 2.04 (m, 2 H, H-2¢, 6¢eq), 2.07 (s, 3 H, 5-CH3), 2.85 (tt,
J = 11.7, 3.7 Hz, 1 H, H-4¢), 3.96 (s, 3 H, OCH3), 3.96 (s, 3 H,
OCH3), 4.30 (s, 2 H, CH2O), 4.60 (s, 2 H, CH2O), 7.41–7.45 (m, 4
H, H-3¢¢), 7.54–7.58 (m, 2 H, H-4¢¢), 8.02–8.05 (m, 4 H, H-2¢¢).
IR (CHCl3): 3629, 3392, 1596, 1566, 1480, 1386, 1100, 1060, 1046,
840 cm–1.
1H NMR (600.13 MHz, DMSO-d6): d = 1.19 (m, 2 H, H-2¢ and H-
6¢a), 1.54–1.63 (m, 6 H, H-2¢b, 6¢b, 3¢, and H-5¢), 2.42 (m, 1 H, H-
4¢), 3.18 (d, J = 5.4 Hz, 2 H, CH2OH), 3.41 (d, J = 5.3 Hz, 2 H,
CH2OH), 3.85 (s, 3 H, 6-OCH3), 3.86 (s, 3 H, 2-OCH3), 4.31 (t,
J = 5.4 Hz, 1 H, OH), 4.35 (t, J = 5.5 Hz, 1 H, OH), 6.39 (s, 1 H, H-
5).
13C NMR (150.92 MHz, DMSO-d6): d = 9.4, 25.6, 29.9, 37.1, 40.9,
53.9, 54.4, 64.1, 70.7, 106.7, 128.4, 129.6, 130.0, 133.0, 133.0,
162.9, 166.4, 166.5, 169.6, 171.3.
HRMS-ESI: m/z [M + H]+ calcd for C29H32N2O6: 505.23331; found:
505.23338.
13C NMR (150.92 MHz, DMSO-d6): d = 26.6, 28.6, 38.5, 45.0,
53.8, 54.4, 61.0, 68.3, 98.0, 164.9, 171.7, 177.0.
HRMS-ESI: m/z [M + H]+ calcd for C14H22N2O4: 283.16523; found:
283.16527.
Removal of Benzoyl Protecting Groups; General Procedure
Finely powdered K2CO3 (0.746 g, 5.4 mmol) was added to a solu-
tion of the respective benzoyl derivative (1.2 mmol) in MeOH (22
mL). The resulting suspension was sonicated in ultrasound bath for
10 min and then stirred at r.t. for 20 h. The solvent was evaporated
and the residue was partitioned between EtOAc (3 × 75 mL) and
H2O (25 mL). The combined organic layers were dried (Na2SO4)
and evaporated. The products were purified by chromatography.
Anal. Calcd for C14H22N2O4: C, 59.56; H, 7.85; N, 9.92. Found: C,
59.55; H, 7.94; N, 9.83.
[4-(2,6-Dimethoxy-5-methylpyrimidin-4-yl)cyclohexane-1,1-
diyl]dimethanol (51)
Prepared from 49. Chromatography: EtOAc–acetone–EtOH–H2O
(20:3:1:1); yield: 66%; white cotton wool like crystals; mp 130.5–
131 °C (EtOAc).
[3-(2,6-Dimethoxypyrimidin-4-yl)cyclohexane-1,1-diyl]dimeth-
anol (43)
Prepared from 41. Chromatography: EtOAc–acetone–EtOH–H2O
IR (CHCl3): 3630, 3402, 1585, 1570, 1476, 1391, 1379, 1370, 1098,
1082, 1042, 532 cm–1.
(20:3:1:1); yield: 92%; colorless oil.
1H NMR (600.13 MHz, DMSO-d6): d = 1.22 (dt, J = 13.8, 4.2 Hz,
2 H, H-2¢, 6¢ax), 1.42 (dm, J = 13.6 Hz, 2 H, H-3¢, 5¢eq), 1.58 (dm,
J = 13.8 Hz, 2 H, H-2¢, 6¢eq), 1.70 (m, 2 H, H-3¢, 5¢ax), 2.00 (s, 3 H,
5-CH3), 2.72 (tt, J = 11.8, 3.7 Hz, 1 H, H-4¢), 3.19 (d, J = 5.5 Hz, 2
H, CH2O), 3.44 (d, J = 5.4 Hz, 2 H, CH2O), 3.84 (s, 3 H, 2-OCH3),
3.87 (s, 3 H, 6-OCH3), 4.33 (t, J = 5.4 Hz, 1 H, OH), 4.35 (t, J = 5.5
Hz, 1 H, OH).
13C NMR (150.92 MHz, DMSO-d6): d = 7.5, 24.1, 26.8, 36.7, 39.1,
52.2, 52.2, 59.1, 66.7, 104.5, 160.9, 167.4, 170.8.
HRMS-ESI: m/z [M + H]+ calcd for C15H24N2O4 + H: 297.18088;
found: 297.18103.
IR (CHCl3): 3628, 3360, 1596, 1567, 1482, 1385, 1100, 1083, 1046,
839 cm–1.
1H NMR (600.13 MHz, CDCl3): d = 1.08 (dt, J = 13.2, 4.5 Hz, 1 H,
H-6ax), 1.29 (t, J = 13.0 Hz, 1 H, H-2ax), 1.32 (m, 1 H, H-4ax), 1.46
(m, 1 H, H-5ax), 1.49 (m, 1 H, H-6eq), 1.55–1.62 (m, 2 H, H-2eq and
H-5eq), 1.77 (dm, J = 12.5 Hz, 1 H, H-4eq), 2.65 (tt, J = 12.5, 3.5 Hz,
1 H, H-3), 3.17 (m, 2 H, CH2O), 3.44 (m, 2 H, CH2O), 3.85 (s, 3 H,
OCH3), 3.86 (s, 3 H, OCH3), 4.34–4.37 (m, 2 H, OH), 6.36 (s, 1 H,
H-5).
13C NMR (150.92 MHz, DMSO-d6): d = 21.1, 28.4, 31.5, 34.3,
39.7, 40.0, 53.8, 54.4, 61.3, 68.6, 98.0, 165.0, 171.7, 177.4.
HRMS-FAB: m/z [M + Na]+ calcd for C14H22N2O4 + Na:
305.14718; found: 305.14690.
Anal. Calcd for C15H24N2O4: C, 60.79; H, 8.16; N, 9.45. Found: C,
60.73; H, 8.20; N, 9.43.
Removal of Methyl Protecting Groups; General Procedure
A mixture of the protected substrate (0.5 mmol), THF (1 mL), 1,4-
dioxane (1 mL), and concd HCl (1.3 mL) was heated to refluxed for
3 h. H2O (5 mL) was added and after refrigerating the resulting mix-
ture for 30 min, the product was collected by filtration, washed with
a mixture of EtOAc and EtOH (2:1, 5 mL) and dried in a vacuum
oven to afford the products.
[3-(2,6-Dimethoxy-5-methylpyrimidin-4-yl)cyclohexane-1,1-
diyl]dimethanol (44)
Prepared from 42. Chromatography: EtOAc–acetone–EtOH–H2O
(20:3:1:1); yield: 89%; white crystals; mp 81–82.5 °C (EtOAc–
toluene).
IR (CHCl3): 3629, 3401, 1585, 1572, 1476, 1391, 1380, 1370, 1109,
1082, 1048, 532 cm–1.
Synthesis 2010, No. 23, 4119–4130 © Thieme Stuttgart · New York

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Convergent Approaches to Carbocyclic C-Nucleosides
4129
6-[3,3-Bis(hydroxymethyl)cyclohexyl]pyrimidine-2,4(1H,3H)-
dione (45)
Prepared from 43. Instead of direct collection of crystals by filtra-
tion, the mixture was evaporated to a minimum volume and crystal-
lized from H2O with a drop of EtOH to give the product in 66%
yield; white crystals; mp 243–245.5 °C (H2O–EtOH).
6-[4,4-Bis(hydroxymethyl)cyclohexyl]-5-methylpyrimidine-
2,4(1H,3H)-dione (53)
Prepared from 51; yield: 79%; white crystals; mp 320–323.5 °C
(THF–1,4-dioxane–H2O).
IR (KBr): 3430, 3286, 3226, 3170, 3105, 1701, 1664, 1511, 1420,
1371, 1037 cm–1.
IR (KBr): 3379, 3229, 3168, 3091, 3048, 1709, 1671, 1656, 1630,
1499, 1399, 1047, 1026, 769 cm–1.
1H NMR (600.13 MHz, DMSO-d6): d = 1.18 (dt, J = 13.5, 4.2 Hz,
2 H, H-3¢, 5¢ax), 1.34 (dm, J = 13.0 Hz, 2 H, H-2¢, 6¢eq), 1.55 (dm,
J = 13.8 Hz, 2 H, H-3¢, 5¢eq), 1.75 (dq, J = 12.9, 3.7 Hz, 2 H, H-2¢,
6¢ax), 1.77 (s, 3 H, 5-CH3), 2.54 (m, 1 H, H-1¢), 3.16 (s, 2 H, CH2O),
3.52 (s, 2 H, CH2O), 4.16 (br s, 1 H, OH), 4.34 (br s, 1 H, OH), 10.42
(br d, J = 1.9 Hz, 1 H, H-1), 10.93 (br d, J = 1.9 Hz, 1 H, H-3).
13C NMR (150.92 MHz, DMSO-d6): d = 9.5, 24.2, 28.8, 38.6, 39.6,
60.9, 68.5, 103.1, 151.5, 154.7, 165.2.
HRMS-ESI: m/z [M + H]+ calcd for C13H21N2O4: 269.14958; found:
269.14966.
1H NMR (499.95 MHz, DMSO-d6): d = 1.07 (dt, J = 13.5, 4.6 Hz,
1 H, H-4¢ax), 1.12 (t, J = 13.0 Hz, 1 H, H-2¢ax), 1.19 (qd, J = 12.7, 3.8
Hz, 1 H, H-6¢ax), 1.38 (qt, J = 13.4, 3.6 Hz, 1 H, H-5¢ax), 1.44 (dm,
J = 14.7 Hz, 1 H, H-4¢eq), 1.52–1.60 (m, 2 H, H-2¢eq and H-5¢eq),
1.74 (dm, J = 12.8 Hz, 1 H, H-6¢eq), 2.38 (tt, J = 12.5, 3.2 Hz, 1 H,
H-1¢), 3.14 (dd, J = 10.4, 5.7 Hz, 1 H, CH2O), 3.17 (dd, J = 10.4, 5.5
Hz, 1 H, CH2O), 3.30–3.45 (m, 2 H, CH2O), 4.29 (t, J = 5.7 Hz, 1
H, OH), 4.36 (t, J = 5.6 Hz, 1 H, OH), 5.26 (d, J = 1.3 Hz, 1 H, H-
5), 10.65 (br s, 1 H, NH), 10.89 (br s, 1 H, NH).
Anal. Calcd for C13H20N2O4·1/8 H2O: C, 57.71; H, 7.54; N, 10.35.
Found: C, 57.73; H, 7.55; N, 10.01.
13C NMR (125.73 MHz, DMSO-d6): d = 21.0, 28.1, 30.1, 33.5,
35.7, 39.8, 61.0, 68.2, 95.9, 151.9, 161.4, 164.6.
HRMS-FAB: m/z [M + Na]+ calcd for C36H56N6O13 + Na:
277.11588; found: 277.11591.
Anal. Calcd for C36H56N6O13.1/6 H2O: C, 56.02; H, 7.18; N, 10.89.
Found: C, 56.32; H, 7.16; N, 10.62.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
6-[3,3-Bis(hydroxymethyl)cyclohexyl]-5-methylpyrimidine-
2,4(1H,3H)-dione (46)
Our thanks are due to Dr. Petra Břehová for her help with separation
of isomers by preparative HPLC and to Ms Jaroslava Sklenářová
for excellent technical assistance. This study, a part of the research
project #Z4 055 0506, was supported by the Ministry of Education
of the Czech Republic (Centre for New Antivirals and Antineo-
plastics # 1M0508), and by Gilead Sciences, Inc. (Foster City, CA,
U.S.A.).
Prepared from 44; yield: 72%; white crystals; mp 286 °C (THF–
1,4-dioxane–H2O).
IR (KBr): 3555, 3375, 3225, 3155, 3084, 3026, 1707, 1660, 1500,
1439, 1427, 1376, 1043 cm–1.
1H NMR (600.13 MHz, DMSO-d6): d = 1.07 (dt, J = 13.7, 3.7 Hz,
1 H, H-4¢ax), 1.37 (dm, J = 13.0 Hz, 1 H, H-2¢eq), 1.43 (t, J = 12.9
Hz, 1 H, H-2¢ax), 1.41–1.50 (m, 3 H, H-4¢eq, H-5¢ax, and H-6¢eq), 1.54
(m, 1 H, H-5¢eq), 1.63 (qd, J = 12.5, 3.9 Hz, 1 H, H-6¢ax), 1.76 (s, 3
H, CH3), 2.82 (tt, J = 12.6, 1.8 Hz, 1 H, H-1¢), 3.15 (m, 2 H, CH2O),
3.43 (m, 2 H, CH2O), 4.35 (t, J = 5.2 Hz, 1 H, OH), 4.38 (t, J = 5.5
Hz, 1 H, OH), 10.19 (d, J = 1.9 Hz, 1 H, H-3), 10.93 (d, J = 1.7 Hz,
1 H, H-1).
13C NMR (150.92 MHz, DMSO-d6): d = 9.4, 21.0, 27.8, 28.0, 31.7,
34.0, 39.5, 60.8, 68.5, 103.1, 151.4, 154.7, 165.2.
HRMS-ESI: m/z [M + Na]+ calcd for C13H20N2O4 + Na: 291.13153;
found: 291.13167.
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6-[4,4-Bis(hydroxymethyl)cyclohexyl]pyrimidine-2,4(1H,3H)-
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