Convergent or linear? A challenging question in carbocyclic nucleoside chemistry

Article abstract of DOI:10.1055/s-2007-990847

North-methanocarbathymidine (N-MCT) is a carbocyclic nucleoside analogue with potent anti-HSV and KSHV activity. The critical step in the synthesis of N-MCT and other carbocyclic nucleoside analogues is the introduction of the nucleobase into the carbocyclic moiety. For this, convergent and linear strategies were compared side by side. In the convergent approach, the base was coupled to the carbocyclic moiety by either a Mitsunobu reaction or by displacement of a mesylate. This strategy leads to the formation of various amounts of the O2-regioisomer, depending on the applied procedure. Additionally, by-products of the Mitsunobu reaction have to be separated from the coupling products. Although lengthier, the linear strategy leads selectively to the target compound N-MCT with overall yields comparable to the convergent approaches, making this strategy more compatible for future large-scale syntheses. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990847

PAPER
3451
Convergent or Linear? A Challenging Question in Carbocyclic Nucleoside
Chemistry
O
ptimizing the Sy
lnthesis
a
of
N
orth-M
f
ethanocarbath
R
ymidine . Ludek, Victor E. Marquez*
Laboratory of Medicinal Chemistry, Center for Cancer Research, National Cancer Institute at Frederick, 376 Boyles Street, Frederick,
MD 21702, USA
Fax +1(301)8466033; E-mail: marquezv@mail.nih.gov
Received 30 May 2007; revised 10 August 2007
O
Abstract: North-methanocarbathymidine (N-MCT) is a carbocy-
clic nucleoside analogue with potent anti-HSV and KSHV activity.
H
H
NH
The critical step in the synthesis of N-MCT and other carbocyclic
nucleoside analogues is the introduction of the nucleobase into the
carbocyclic moiety. For this, convergent and linear strategies were
compared side by side. In the convergent approach, the base was
coupled to the carbocyclic moiety by either a Mitsunobu reaction or
by displacement of a mesylate. This strategy leads to the formation
of various amounts of the O2-regioisomer, depending on the applied
procedure. Additionally, by-products of the Mitsunobu reaction
have to be separated from the coupling products. Although lengthi-
er, the linear strategy leads selectively to the target compound N-
MCT with overall yields comparable to the convergent approaches,
making this strategy more compatible for future large-scale synthe-
ses.
HO
N
convergent
linear
AcO
O
OH
HO
AcO
?
1
2
Figure 1 Strategies for carbocyclic nucleoside synthesis
The starting point of this investigation was the necessity
for a high-yielding and convenient synthesis for the car-
bocyclic nucleoside north-methanocarbathymidine (1, N-
MCT).3 N-MCT (1) is a thymidine analogue, based on a
bicyclo[3.1.0]hexane template4 locked in the northern
conformation as defined in the pseudorotational cycle.5
The concept of locked nucleosides with this scaffold was
originally introduced to investigate the conformational
preferences of various enzymes, particularly kinases and
polymerases.6 However, besides their role as molecular
probes, some conformationally restricted nucleosides
showed interesting antiviral properties.7 Among these, N-
MCT (1) was found to exhibit greater antiherpetic activity
against herpes virus types 1 (HSV-1), 2 (HSV-2),8 and
Kaposi’s sarcoma-associated herpesvirus (KSHV)9 than
the reference compounds acyclovir, gancyclovir, and ci-
dofovir. Additionally, the nucleoside triphosphate (N-
MCT-TP) is a potent inhibitor of HIV replication by act-
ing as a delayed chain terminator.10 These outstanding
antiviral properties make N-MCT (1) an interesting mole-
cule for clinical studies. Therefore, a high-yielding and se-
lective synthetic route is highly desirable.
Key words: medicinal chemistry, nucleosides, carbocycles, Mit-
sunobu reaction, regioselectivity
The key synthetic step in carbocyclic nucleoside chemis-
try is the condensation of the pseudosugar moiety with the
heterocyclic nucleobase (Figure 1). Over the last decades,
a number of strategies to achieve this goal, which can be
classified into two major categories as convergent and lin-
ear, have been developed.1 In the convergent approach,
the complete nucleobase is coupled directly to an activat-
ed carbocycle, opening the opportunity for the rapid syn-
thesis of a variety of carbocyclic nucleosides. This is
especially desired if nucleosides built on a specific car-
bocycle are to be screened for biological activity.2 Unfor-
tunately, nucleobases can react as ambident nucleophiles,
leading to mixtures of isomers (N1- and O2-regioisomers
for pyrimidines and N7- and N9-regioisomers for purines)
and their separation can be a challenging and time-con-
suming task. In the linear approach, a pre-functionalized
carbocyclic amine is prepared and then subsequently
modified by the step-wise build-up of the heterocyclic
base. By applying this strategy, only one of the possible
regioisomers is obtained; however, each nucleoside ana-
logue requires a separate multistep synthesis. In this pa-
per, we report on the direct comparison of both
approaches and focus on their discrete advantages and dis-
advantages with respect to both lab-scale and larger-scale
reactions.
Convergent Strategy: Introduction of the Nucleobase
by Mitsunobu Chemistry
As starting material for our investigations, we chose the
bicyclic hexanol 2, which can be obtained in high optical
purity by the previously reported procedure.11 For the con-
vergent approach, 2 was coupled directly with the N3-pro-
tected thymines 312 and 413 under Mitsunobu conditions14
(Figure 2).
As mentioned before, pyrimidine bases can react as ambi-
dent nucleophiles and mixtures of N1- and O2-alkylated
products are generally obtained under Mitsunobu condi-
tions. The product ratio seems to be dependent upon the
SYNTHESIS 2007, No. 22, pp 3451–3460
x
x.
x
x
.
2
0
0
7
Advanced online publication: 29.10.2007
DOI: 10.1055/s-2007-990847; Art ID: M03807SS
© Georg Thieme Verlag Stuttgart · New York

3452
O. R. Ludek, V. E. Marquez
PAPER
O
O
O
O
ration of the solvent. A small sample was dissolved in
CDCl3 and the solutions were analyzed by 1H NMR spec-
troscopy. The ratios were obtained after integration of the
respective signals of the H-4¢ protons, which appear as
distinctive doublets at 4.96 (N1) and 5.29 (O2) ppm
(Figure 3).
N
O
N
N
O
N
H
H
4
3
Figure 2 N3-Protected thymines for use in Mitsunobu couplings
reaction temperature,15 solvent,16 protected nucleobase,17
the alcohol itself,18 and the order in which the components
are added to each other.19 In this study, we followed a re-
liable Mitsunobu-protocol developed for the synthesis of
carbocyclic nucleosides with the natural deoxyribo-con-
figuration, which predominantly leads to the desired N1-
alkylated regioisomers.20 Recent studies on the influence
of the protecting group on the heterocycle have shown
that the benzyloxymethyl group (BOM) on N3 of pyrim-
idines leads to an improved product N1/O2 ratio17b com-
pared to the standard benzoyl protected derivative 3. In
this study, both nucleophiles were evaluated for their cou-
pling behavior. For this, the pre-formed complex from
triphenylphosphine and diisopropylazodicarboxylate
(DIAD) was added slowly to a mixture of the starting ma-
terial 2 and the protected nucleobase in acetonitrile, since
polar solvents seem to favor N1-alkylation16b (Scheme 1).
Overall, coupling yields for both procedures were compa-
rable: 79% of 1 and 5 (for 3) and 76% of 6 and 7 (for 4).
As expected, the BOM-protected base 4 yielded 10%
more of the desired N1-product than that obtained from
the classic N3-benzoyl derivative 3. However, the extra
hydrogenation step to remove the BOM group lowered the
Figure 3 Determination of the product distribution by 1H NMR
spectroscopy from the crude reaction mixture
A major drawback of the Mitsunobu approach is the poor
atom economy of the reaction, making it unattractive for
larger-scale syntheses.21 Triphenylphosphine and DIAD
are only used to activate the hydroxy group for the subse-
quent nucleophilic displacement, and inevitably result in
the formation of by-products such as triphenylphosphine
oxide and diisopropylhydrazine dicarboxylate (DIHD)
that have to be separated from the desired compounds.
These by-products are insoluble in aqueous media and
therefore have to be removed by chromatography.22
Convergent Strategy: Introduction of the Heterocycle
by Displacement of a Mesylate
overall yield somewhat giving 56% of 1 compared to 60% To overcome the formation of by-products, we decided to
obtained from using 3. In both cases, the N1- and O2-re- investigate the possibility to introduce the base by nucleo-
gioisomers were easily separated by regular column chro- philic displacement of a mesylate on the carbocyclic moi-
matography on silica gel. The product distributions were
determined from the crude reaction mixtures after evapo-
ety. This approach is not new and a lot of nucleoside
analogues have been synthesized by displacing other leav-
O
N
O
HN
NH
O
H
H
HO
N
HO
O
+
a, b
76%
24%
79%
HO
HO
1
5
H
AcO
e
87%
OH
AcO
O
O
2
BOMN
O
NBOM
H
H
c, d
HO
N
HO
N
+
O
76%
HO
15%
85%
HO
7
6
Scheme 1 Reagents and conditions: (a) Ph3P, DIAD, 3, MeCN, –40 °C to r.t., 15 h; (b) 1% NaOH in MeOH, r.t., 15 h; (c) Ph3P, DIAD, 4,
MeCN, –40 °C to r.t., 15 h; (d) Amberlite OH–, MeOH, r.t. 5 h; (e) H2, Pd/C, MeOH, r.t., 15 h.
Synthesis 2007, No. 22, 3451–3460 © Thieme Stuttgart · New York

PAPER
Optimizing the Synthesis of North-Methanocarbathymidine
3453
ing groups such as halides,23 sulfonates,24 or opening of
epoxides25 with deprotonated nucleobases. However, the
yields are usually low due to side reactions and the low
solubility of the nucleobase salts in organic solvents. To
increase the solubility and to minimize side reactions, we
decided to investigate the behavior of the protected thym-
ine analogues 3 and 4 developed for the coupling with
Mitsunobu chemistry in simple displacement reactions.
Surprisingly, only very few examples of this straightfor-
ward coupling strategy can be found in the literature.26
Howarth et al. reported on the substitution of brosylates
Table 1 Condensation of the Mesylate 8 with 3-N-BOM-thymine 4
at Different Temperaturesa
Entry
Temp
(°C)
Time
(h)
Yield (%)
9a + 9b
Ratio
(N1/O2, %)b
1
2
3
4
80
60
40
20
1
2
79
81
77
79
75:25
78:22
80:20
84:16
16
56
and iodides by N3-benzoylthymine for the synthesis of a- a All reactions were performed with 3.0 equiv of KHMDS and 3.0
equiv of heterocycle 4.
cycloPNAs in moderate yields. Unfortunately, no com-
b Determined by integration of the H-4¢ and 5-CH3 protons of the prod-
ments were made on the formation of O2-alkylated prod-
ucts from the crude reaction mixture.
ucts and product ratios.26c Since we believe that this is the
‘Achilles heel’ of any convergent approach, it encouraged
Optimization of the Reaction Conditions
us to look at this strategy in more detail. In a first attempt,
the bicyclic hexanol 2 was converted to its methanesulfo-
nyl ester 8 by reaction with mesyl chloride in dichlo-
romethane in the presence of triethylamine (Scheme 2).
These promising results led us to investigate whether the
product ratio could possibly be further fine-tuned to favor
the N1-product by varying the reaction conditions. There-
fore, the influence of the counterion and the solvent were
examined in simple NMR experiments. For the carbocy-
clic moiety, cyclopentyl iodide was chosen as a model
compound, since it produced comparable product ratios to
the mesylate 8 under similar reaction conditions (Table 2).
In addition, the observed NMR spectra were significantly
simplified, making product-ratio determination a straight
forward task.
O
H
H
NBOM
AcO
AcO
N
b
1'
4'
O2-alkylated
O
OR
a
see
Table 1
+
product (9b)
AcO
AcO
9a
R = H: 2
quant.
In polar aprotic solvents, anionic nucleophiles tend to
form ion-pair aggregations with their cations, reducing the
rate of attack on the electrophile. By varying the cation,
the dissociation constants of these ion-pairs change, re-
sulting in different concentrations of free nucleophile and
therefore different rate constants can be observed.27 This
phenomenon is especially interesting when ambident nu-
cleophiles are used, since both reaction centers might be
influenced differently, possibly resulting in a change of
product ratios.
R = Ms: 8
Scheme 2 Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0 °C
to r.t., 1 h; (b) KHMDS, 4, DMF.
This conversion is quantitative and the crude product ob-
tained from simple extractive workup is sufficiently pure
to be used for the following reactions. Attempts to further
purify the mesylate 8 by chromatography failed and only
products resulting from decomposition on the column
were observed. When stored at –20 °C, the activated car-
bocycle 8 is stable for weeks, but storage at room temper-
ature should be avoided. After deprotonation of 3-N-BOM
thymine 4 with KHMDS in DMF, the mesylate 8 was add-
ed and the clear solution was stirred at different tempera-
tures, until complete consumption of the starting material
8 was observed by TLC (Table 1).
To study the influence of the cation, the protected hetero-
cycles 3 and 4 were deprotonated by various bases in per-
deuterated DMF. After addition of cyclopentyl iodide, the
mixtures were stirred for the indicated time and product
ratios were determined by integration of the H-1¢ and/or
CH3 protons of the base. The results of these experiments
are summarized in Table 2.
After extractive workup, the crude material was analyzed
by 1H NMR and the product ratio was determined by inte-
gration of the respective H-4¢ and/or 5-methyl protons.
Obviously, an increase in temperature results in shorter
reaction time, but also in decreased selectivity. At room
temperature, this method produced the same product ratio
observed for the Mitsunobu coupling with this base. To-
gether with good overall coupling yields, this strategy can
be considered as a powerful alternative to Mitsunobu
chemistry, especially when removal of triphenylphos-
phine oxide and DIHD is a problem. Moreover, less waste
is created, making this procedure also attractive from an
ecological and economical point of view.
In case of the 3-N-benzoyl derivative 3 a slight depen-
dence of the product ratio due to the counterion could be
observed (Table 2, entries 1–5), with Cs2CO3 being the
most effective inorganic base (entry 2). Complexation of
the potassium cation with 18-crown-6 (entry 5) led to a
marked decrease in the reaction time, possibly due to
higher concentrations of ‘free’ nucleophile in the reaction
mixture. Remarkably, all bases examined for deprotona-
tion of the heterocycle 4 resulted in the same product ratio
within the experimental error (entries 6–14). Although no
change in selectivity was observed, the lipophilic counter-
ions tetramethylammonium and tetrabutylammonium28
Synthesis 2007, No. 22, 3451–3460 © Thieme Stuttgart · New York

3454
O. R. Ludek, V. E. Marquez
PAPER
Table 2 Influence of the Counterion on the Alkylation of Pyrimidine Nucleobases 3 and 4a
O
N
base
R
O
3 (R = Bz) or
4 (R = BOM)
4 Å MS
R
N
N
N
O
I
+
O
DMF-d7
1'
1'
N1
O2
Entry
1
Heterocycle
Base
Temp
r.t.
Time (h)
Ratio (N1/O2, %)b
3
3
3
3
3
4
4
4
4
4
4
4
4
4
K2CO3
Cs2CO3
LiOH
16
16
16
16
2
88:12
93:7
2
r.t.
3
r.t.
92:8
4
CsOH·H2O
r.t.
91:9
5
K2CO3 + 18-crown-6
KHMDS
r.t.
93:7
6
60 °C
60 °C
r.t.
2
88:12
87:13
87:13
87:13
87:13
86:14
89:11
88:12
87:13
7
K2CO3
2
8
K2CO3
16
16
16
16
2
9
Cs2CO3
r.t.
10
11
12
13
14
LiOH
r.t.
CsOH·H2O
Me4NOH
r.t.
r.t.
Bu4NOH
r.t.
2
K2CO3 + 18-crown-6
r.t.
2
a All reactions were performed with 3.0 equiv of base and 3.0 equiv of heterocycle.
b Determined by integration of the H-1¢ and 5-CH3 protons of the products from the crude reaction mixture in DMF-d7.
(entries 12 and 13), as well as the complexing agent 18- As already observed for the coupling under Mitsunobu
crown-6 (entry 14) led, as in the case of 3, to a drastic de- conditions,16b the applied solvent has a major influence on
crease in reaction times.
the outcome of the product distribution. The higher the
polarity and therefore the ability to solvate cations, the
more of the desired N1-product is formed. Certainly, the
N1-position is the more basic reaction center in the nu-
cleobase derivatives 3 and 4, since it is the primary site of
alkylation by the electrophile when free from interactions
with the cation (Table 3, entries 1,2,6 and 7). As the polar-
ity decreases from DMSO to dichloromethane (entries 1–
5 and 6–10), the ability of the solvent to solvate cations is
also reduced, and the more basic atom becomes increas-
ingly encumbered by the counterion. This leaves the less
basic center free for interaction with the electrophile and
the product distribution changes in favor of the O2-prod-
uct. In addition, the ion-pairing in solvents of low polarity
results in very low concentrations of free nucleophile, and
only slow or no reactions were observed (entries 4,5, and
8–10).
Besides the counterion of the anionic nucleophile, the sol-
vent is a critical factor in nucleophilic substitution reac-
tions.29 It stabilizes the transition state and forms a cage of
solvent molecules around the nucleophile. The influence
of the solvent on the regioselectivity in substitution reac-
tions with ambident nucleophiles is based upon the differ-
ences in solvation of the reagent in different solvents.
Therefore, the relative nucleophilicity of the attacking at-
oms can also be different, leading to changes in the prod-
uct ratio. In aprotic solvents, the position with the higher
electron density is usually more basic, reacting predomi-
nantly with the electrophilic substrate.
To study the influence of the solvent, the protected hetero-
cycles 3 and 4 were treated with potassium carbonate in
various aprotic solvents of different polarities. After the
addition of cyclopentyl iodide, the mixtures were stirred
for the indicated time. The solvents were then evaporated
off and the residues were redissolved in CDCl3. The prod-
uct ratios were again determined by integration of the H-
1¢ and/or 5-CH3 protons. The results of these experiments
are summarized in Table 3.
The best reaction conditions and reagents utilized in these
model reactions were applied to the coupling of the pro-
tected bases 3 and 4 with the bicyclic mesylate 8. Because
nucleophiles with lipophilic counterions greatly acceler-
ate substitution reactions, 8 was treated with tetramethyl-
ammonium or crown-ether potassium salts of the
Synthesis 2007, No. 22, 3451–3460 © Thieme Stuttgart · New York

PAPER
Optimizing the Synthesis of North-Methanocarbathymidine
3455
Table 3 Influence of the Solvent on the Alkylation of Pyrimidine Nucleobases 3 and 4a
K2CO3
O
N
R
O
3 (R = Bz) or
4 (R = BOM)
4 Å MS
R
N
N
N
O
I
+
O
solvent
1'
1'
N1
O2
Entry
Heterocycle
Solventb
DMSO
DMF
Time (h)
16
Ratio (N1/O2, %)c
1
2
3
3
3
3
3
4
4
4
4
4
95:5
16
88:12
75:25
38:62d
only O2 productd
91:9
3
MeCN
acetone
CH2Cl2
DMSO
DMF
16
4
16
5
16
6
16
7
16
87:13
n.r.e
8
MeCN
acetone
CH2Cl2
24
9
24
n.r.e
10
24
n.r.e
a All reactions were performed with 3.0 equiv of K2CO3 and 3.0 equiv of heterocycle.
b Decreasing polarity from DMSO to CH2Cl2.
c Determined by integration of the H-1¢ and 5-CH3 protons of the products from the crude reaction mixture.
d Incomplete reaction (TLC).
e No reaction (TLC).
nucleobases 3 and 4 in polar solvents (DMF or DMSO) the same manner after the coupling under Mitsunobu con-
(Table 4). The product ratio was determined by integra- ditions, led to the target molecule N-MCT (1) (results not
tion of the respective H-4¢ and 5-methyl protons in the shown).
crude mixtures after extraction with diethyl ether. During
As expected, the reactions were again greatly accelerated
extraction, the high-boiling solvents DMSO and DMF re-
by lipophilic counterions. Even when the amount of nu-
mained in the aqueous phase, greatly facilitating the
cleophile was decreased to 1.5 equivalents (entry 4), the
workup. Removal of the protecting groups, performed in
Table 4 Condensation of the Mesylate 8 with the Protected Thymines 3 and 4 under Optimized Conditionsa
O
H
H
N
R
N
AcO
AcO
AcO
AcO
O2-alkylated
product (9b/10b)
1' 4'
+
O
OMs
R = BOM: 9a
8
R = Bz: 10a
Entry Heterocycle Base
Solvent
DMF
Time (h)
Product
10a/b
10a/b
9a/b
Yield (%)b
Ratio (N1/O2, %)c
89:11
1
3
3
4
4
4
K2CO3 + 18-crown-6
16
24
16
36
16
79
44
81
78
79
2
Cs2CO3
DMSO
DMF
87:13
3
Me4NOH
82:18
4d
5
Me4NOH
DMF
9a/b
82:18
K2CO3 + 18-crown-6
DMSO
9a/b
85:15
a All reactions were performed with 3.0 equiv of base and 3.0 equiv of heterocycle at r.t., unless indicated otherwise.
b Isolated yield of both regioisomers.
c Determined by integration of the H-4¢ (carbocycle) and 5-CH3 (base) protons of the crude products
d With 1.5 equiv of base and heterocycle.
Synthesis 2007, No. 22, 3451–3460 © Thieme Stuttgart · New York

3456
O. R. Ludek, V. E. Marquez
PAPER
a
2
H
H
75%
AcO
N3
AcO
NH2
c
quant.
b
AcO
O
AcO
8
11
12
73%
O
O
H
NCO
13
H
AcO
N
NH
e
d
O
1
83%
O
85%
AcO
14
Scheme 3 Reagents and conditions: (a) DPPA, Et3N, DMF, 60 °C, 20 h; (b) NaN3, DMF, 90 °C, 1 h; (c) H2, Lindlar cat., MeOH–CH2Cl2
(1:1), 16 h; (d) DMF–benzene 1:1, 0 °C to r.t., 16 h; (e) 2 N HCl, EtOH, 80 °C, 16 h.
reaction proceeded with sufficient speed with no change large-scale syntheses. Furthermore, when separation of
in the product ratio. The use of Cs2CO3 in DMSO (Table the regioisomers is a problem, the classic linear strategy
4, entry 2) in combination with heterocycle 3 resulted in should be the method of choice.
the lowest isolated coupling yields (44%). TLC-analysis
of the reaction showed multiple products, probably result-
All experiments involving moisture-sensitive compounds were con-
ing from elimination and decomposition. The best result
in terms of overall yield (79%) and product distribution
(89% N1/11% O2) was obtained by using heterocycle 3 to-
gether with potassium carbonate and 18-crown-6 in DMF
(entry 1). The reaction proceeded smoothly and no side
products were detected by TLC analysis. Since the exper-
imental procedure is straightforward and leads to excel-
lent product distributions, this method should be
considered as alternative to the common Mitsunobu ap-
proach.
ducted under dry conditions (positive argon pressure) using stan-
dard syringe, cannula, and septa apparatus. Solvents: All solvents
were purchased anhydrous (Aldrich) and stored over activated mo-
lecular sieves. HPLC-grade hexanes, EtOAc, CH2Cl2, and MeOH
were used in chromatography. Chromatography: Chromatotron
(Harrison Research 7924T), Analtech rotors (silica gel GF), UV de-
tection at 254 nm; flash chromatography was performed with Tele-
dyne ISCO CombiFlash Companion. TLC: analytical TLC was
performed on Analtech precoated plates (Uniplate, silica gel GHLF,
250 microns) containing a fluorescence indicator; sugar-containing
compounds were visualized with the sugar spray reagent [4-meth-
oxybenzaldehyde (5 mL), EtOH (90 mL), concd H2SO4 (5 mL), and
glacial AcOH (10 mL)] by heating with a heat gun. NMR spectra
were recorded using a Varian Inova 400 MHz spectrometer. The
coupling constants are reported in Hertz, and the peak shifts are re-
ported in the d (ppm) scale. Mass spectra (FABMS) were obtained
on a VG 7070E mass spectrometer at an accelerating voltage of 6
kV and a resolution of 2000. Glycerol was used as the sample ma-
trix, and ionization was effected by a beam of xenon atoms. Optical
rotations were measured on a Jasco P-1010 polarimeter at 589 nm.
Formation of the Heterocycle by a Linear Approach
To compare the results obtained from the convergent ap-
proaches with the linear strategy, the bicyclic hexanol 2
had to be converted to the bicyclic amine 12 with inverted
stereochemistry at C-4. Therefore, the alcohol 2 was re-
acted with diphenylphosphoryl azide (DPPA) in DMF to
yield the azido compound 11 with inversion of configura-
tion (75%) (Scheme 3). Alternatively, the mesylate 8 can IR spectra were obtained neat with a Jasco FT-IR/615 spectrometer.
Elemental analyses were performed by Atlantic Microlab. Inc.,
be treated with sodium azide in DMF, yielding the azide
Norcross, Georgia, 30091, USA.
11 in 73%. The azide 11 was then quantitatively reduced
to the amine 12 by hydrogenation in methanol–dichlo-
romethane (1:1) over Lindlar’s catalyst. This amine 12
Convergent Strategy: Introduction of the Nucleobase by Mit-
sunobu Chemistry
was subsequently reacted with the acylisocyanate 13 in
DMF (85%), prepared freshly from 3-methoxy-2-methyl-
acryloyl chloride30 and silver isocyanate in benzene. Ring
closure of urea 14 under aqueous acidic conditions (83%)
also cleaved the acetate protecting groups, yielding the fi-
nal compound N-MCT (1) in 53% overall yield (for
DPPA route), starting from the bicyclic hexanol 2. This
overall yield is only slightly lower than the results ob-
tained for the convergent approaches by Mitsunobu chem-
istry and regular displacement reactions (vide supra).
Taking into consideration that each step can be purified by
simple extraction, all crude materials can be used for the
ensuing reactions. This strategy is especially valuable for
1-[(1¢S,2¢S,4¢S,5¢R)-4¢-Hydroxy-5¢-(hydroxymethyl)bicy-
clo[3.1.0]hexan-2¢-yl]-5-methylpyrimidine-2,4(1H,3H)-dione
(N-MCT, 1)
To a suspension of Ph3P (344 mg, 1.31 mmol) in anhyd MeCN, 5.0
mL) was added slowly diisopropylazodicarboxylate (DIAD, 238
mL, 1.23 mmol) and the mixture was stirred for 0.5 h at 0 °C. This
preformed complex was slowly added to a suspension of the 3-N-
Bz-thymine 3 (253 mg, 1.10 mmol) and the bicyclic hexanol 2 (100
mg, 0.44 mmol) in anhyd MeCN (3.0 mL) at –40 °C under argon.
The reaction was slowly warmed to r.t. (about 4 h) and stirred over-
night. The solvent was removed from the mixture and the residue
was dissolved in a 1% solution of NaOH in MeOH (10 mL). The
mixture was stirred overnight at r.t. The mixture was neutralized by
the addition of aq 2 N HCl and the solvent was removed under re-
duced pressure. The crude product was purified on a Chromatotron
Synthesis 2007, No. 22, 3451–3460 © Thieme Stuttgart · New York

PAPER
Optimizing the Synthesis of North-Methanocarbathymidine
3457
(MeOH in CH2Cl2, 5–15%) to yield N-MCT (1; 65 mg, 59%) as a
colorless foam.
CHH-benzyl), 4.57 (d, J = 12.0 Hz, 1 H, CHH-benzyl), 3.65 (dd,
J = 11.5, 6.6 Hz, 1 H, CHHOH), 3.54 (dd, J = 11.5, Hz, 4.0 Hz, 1
H, CHHOH), 2.15 (ddd, J = 15.2, 8.2, 1.0 Hz, 1 H, H-3¢a), 2.13 (d,
J = 4.4 Hz, 1 H, 4-OH), 2.00 (dd, J = 6.6, 4.4 Hz, 1 H, CH2OH),
1.92 (d, J = 1.0 Hz, 3 H, CH3), 1.53–1.45 (m, 2 H, H-3¢b, H-1¢), 0.85
(dd, J = 5.9, 4.0 Hz, 1 H, H-6¢a), 0.62 (dd, J = 8.6, 5.9 Hz, 1 H, H-
6¢b).
1H NMR (400 MHz, D2O): d = 7.68 (q, J = 1.0 Hz, 1 H, H-6), 4.71
(d, J = 7.2 Hz, 1 H, H-2¢), 4.65 (dd, J = 8.5, 8.5 Hz, 1 H, H-4¢), 4.02
(d, J = 12.5 Hz, 1 H, CHHOH), 3.22 (d, J = 12.5 Hz, 1 H, CHHOH),
1.90 (dd, J = 15.5, 8.5 Hz, 1 H, H-3¢a), 1.71 (d, J = 1.0 Hz, 3 H,
CH3), 1.64–1.55 (m, 1 H, H-3¢b), 1.35 (dd, J = 8.7, 3.8 Hz, 1 H, H-
1¢), 0.78 (dd, J = 6.0, 3.8 Hz, 1 H, H-6¢a), 0.65 (dd, J = 8.7, 6.0 Hz,
1 H, H-6¢b).
APCI-MS: m/z (%) = 373 (40), 247 (100).
1-[(1¢S,2¢S,4¢S,5¢R)-4¢-Hydroxy-5¢-(hydroxymethyl)bicy-
clo[3.1.0]hexan-2¢-yl]-5-methylpyrimidine-2,4(1H,3H)-dione
(N-MCT, 1)
13C NMR (100 MHz, D2O): d = 166.37 (C-4), 152.13 (C-2), 139.26
(C-6), 110.72 (C-5), 70.57 (C-4¢), 62.17 (CH2OH), 56.75 (C-2¢),
36.63 (C-5¢), 35.76 (C-3¢), 24.76 (C-1¢), 11.39 (CH3), 9.57 (C-6¢).
The BOM-protected nucleoside 6 (50 mg, 0.135 mmol) was dis-
solved in MeOH (5.0 mL) and 10% Pd/C (10 mg) was added. The
flask was flushed with H2 and the mixture was stirred overnight un-
der a H2 atmosphere. The catalyst was filtered off over a short pad
of Celite and the filtrate was concentrated under reduced pressure.
The crude was purified on a Chromatotron (MeOH in CH2Cl2 5–
15%) to yield the title compound 1 (30.0 mg, 87%) as a colorless
foam. The spectroscopic data were identical to those reported
above.
Anal. Calcd for C12H16N2O4·0.25 H2O: C, 56.13; H, 6.48; N, 10.91.
Found: C, 56.12; H, 6.46; N, 10.73.
All other spectroscopic data were identical to those reported earli-
er.7a
3-(Benzyloxymethyl)-1-[(1¢S,2¢S,4¢S,5¢R)-4¢-hydroxy-5¢-(hy-
droxymethyl)bicyclo[3.1.0]hexan-2¢-yl]-5-methylpyrimidine-
2,4(1H,3H)-dione (6) and 3-(Benzyloxymethyl)-2-
[(1¢S,2¢S,4¢S,5¢R)-4¢-hydroxy-5¢-(hydroxymethyl)bicy-
Convergent Strategy: Introduction of the Heterocycle by Dis-
placement of a Mesylate
[(1R,2S,4R,5S)-2-Acetoxy-4-(methylsulfonyloxy)bicy-
clo[3.1.0]hexan-1-yl]methyl Acetate (8)
The bicyclic hexanol 2 (60.0 mg, 0.236 mmol) was dissolved in an-
hyd CH2Cl2 (2 mL) under argon at 0 °C and Et3N (110 mL, 0.789
mmol) and MeSO2Cl (MsCl, 30.5 mL, 0.394 mmol) were slowly
added. The mixture was stirred for 1 h at 0 °C and then poured into
a mixture of ice-cold phosphate buffer (pH, 7.2, 25 mL) and Et2O
(25 mL). The aqueous phase was extracted with Et2O (2 × 20 mL)
and the combined extracts were dried (Na2SO4) and concentrated.
The crude mesylate 2 was used in the next substitution reaction
without any further purification (decomposition occurred during
chromatography on silica gel).
clo[3.1.0]hexan-2¢-yloxy]-5-methylpyrimidin-4(3H)-one (7)
To a suspension of Ph3P (344 mg, 1.31 mmol) in anhyd MeCN (5.0
mL) was added slowly diisopropylazodicarboxylate (DIAD, 238
mL, 1.23 mmol) and the mixture was stirred for 0.5 h at 0 °C. This
preformed complex was slowly added to a suspension of the 3-N-
BOM-thymine 4 (271 mg, 1.10 mmol) and the bicyclic hexanol 2
(100 mg, 0.44 mmol) in anhyd MeCN (3.0 mL) at –40 °C under N2.
The reaction was slowly warmed to r.t. (about 4 h) and stirred over-
night. The solvent was removed from the mixture and the residue
was dissolved in MeOH (10 mL). To this solution was added Am-
berlite IRA-400 (OH–) ion-exchange resin and the mixture was
stirred overnight at r.t. The resin was filtered off and the MeOH was
removed under reduced pressure. The crude product was purified on
a Chromatotron (MeOH in CH2Cl2, 0–10%) to yield the title com-
pounds 6 (106 mg, 65%) and 7 (19 mg, 11%) as colorless syrups,
with 6 eluting prior to 7.
IR (neat): 3019, 2941, 1733, 1446, 1351, 1237, 1171, 1032, 970,
922, 846 cm–1.
1H NMR (400 MHz, CDCl3): d = 5.20 (dd, J = 7.8, 7.8 Hz, 1 H, H-
2), 5.17–5.11 (m, 1 H, H-4), 4.20 (d, J = 12.0 Hz, 1 H, CHHOAc),
3.78 (d, J = 12.0 Hz, 1 H, CHHOAc), 2.94 (s, 3 H, CH3SO3), 2.63
(ddd, J = 14.1, 7.8, 7.8 Hz, 1 H, H-3a), 1.99 (s, 3 H, OCOCH3), 1.98
(s, 3 H, OCOCH3), 1.83–1.78 (m, 1 H, H-3b), 1.25 (dd, J = 6.0, 4.3
Hz, 1 H, H-6a), 0.81 (dd, J = 7.0, 7.0 Hz, 1 H, H-6b).
N1-Alkylated Product 6
[a]D20 +17.91 (c = 0.875, CHCl3).
IR (neat): 3430, 3075, 2926, 1698, 1632, 1466, 1361, 1286, 1244,
1159, 1069, 927 cm–1.
1H NMR (400 MHz, CDCl3): d = 7.57 (q, J = 1.0 Hz, 1 H, H-6),
7.35–7.20 (m, 5 H, CH-arom), 5.47 (s, 2 H, OCH2N), 4.85 (dd,
J = 8.2, 8.2 Hz, 1 H, H-4¢), 4.85 (d, J = 7.3 Hz, 1 H, H-2¢), 4.67 (s,
2 H, CH2-benzyl), 4.18 (d, J = 11.3 Hz, 1 H, CHHOH), 3.42 (d,
J = 11.3 Hz, 1 H, CHHOH), 1.98 (dd, J = 15.2, 8.2 Hz, 1 H, H-3¢a),
1.87 (d, J = 1.0 Hz, 3 H, CH3), 1.78–1.68 (m, 1 H, H-3¢b), 1.33 (dd,
J = 8.6, 3.8 Hz, 1 H, H-1¢), 0.88 (dd, J = 6.0, 3.8 Hz, 1 H, H-6¢a),
0.68 (dd, J = 8.6, 6.0 Hz, 1 H, H-6¢b).
13C NMR (100 MHz, CDCl3): d = 163,51 (C-4), 151.50 (C-2),
137.95 (Cq-arom), 136.65 (C-6), 128.25, 127.62 (CH-arom),
109.94 (C-5), 72.27 (CH2-benzyl), 71.44 (C-4¢), 70.34 (OCH2N),
64.11 (CH2OH), 57.91 (C-2¢), 38.46 (C-5¢), 36.61 (C-3¢), 25.64 (C-
1¢), 13.12 (CH3), 10.21 (C-6¢).
FAB-MS: m/z (%) = 307 (5), 247 (24), 211 (100).
Displacement of Mesylates by N3-Protected Pyrimidines; Gen-
eral Procedures
Method A (for N3-alkylated or acylated pyrimidines): The N3-pro-
tected pyrimidine (3 or 4, 3.0 equiv) was dissolved in anhyd DMF
or DMSO (7 mL/mmol) at r.t. under argon. Powdered 4 Å molecular
sieves (300 mg/mmol), K2CO3 (3.0 equiv) and 18-crown-6 (3.0
equiv) were added and the mixture was stirred for 15 min at r.t. The
mesylate 8 (1.0 equiv) was dissolved in anhyd DMF or DMSO (7
mL/mmol) and then added dropwise to the deprotonated nucleo-
base. The mixture was stirred at r.t. until all the starting material was
consumed according to TLC. The mixture was poured into a mix-
ture of phosphate buffer (pH 7.2, 2 mL) and Et2O (20 mL), and the
aqueous phase was extracted with Et2O (2 × 10 mL). The combined
organic extracts were dried (MgSO4) and concentrated. The crude
materials were purified by flash chromatography yielding the pro-
tected nucleoside analogues as colorless syrups.
ESI-MS: m/z = 373 (M + H), 395 (M + Na), 411 (M + K).
Anal. Calcd for C20H24N2O4·H2O: C, 61.53; H, 6.71; N, 7.18.
Found: C, 61.46; H, 6.41; N, 7.20.
O2-Alkylated Product 7
1H NMR (400 MHz, CDCl3): d = 7.40 (q, J = 1.0 Hz, 1 H, H-6),
7.35–7.20 (m, 5 H, CH-arom), 5.52 (d, J = 10.0 Hz, 1 H, OCHHN),
5.39 (d, J = 10.0 Hz, 1 H, OCHHN), 5.33 (d, J = 5.5 Hz, 1 H, H-2¢),
4.80 (ddd, J = 8.2, 8.2, 4.4 Hz, 1 H, H-4¢), 4.61 (d, J = 12.0 Hz, 1 H,
Method B (for N3-alkylated pyrimidines): The tetraalkylammonium
salt of the BOM-protected nucleobase 4 (3.0 equiv) was dissolved
in anhyd DMF or DMSO (7 mL/mmol) at r.t. under an atmosphere
Synthesis 2007, No. 22, 3451–3460 © Thieme Stuttgart · New York

3458
O. R. Ludek, V. E. Marquez
PAPER
of argon and powdered 4 Å molecular sieves (300 mg/mmol) were
added. After the addition of the mesylate 8 (1.0 equiv), dissolved in
anhyd DMF or DMSO (7 mL/mmol), the mixture was stirred until
all the starting material was consumed as monitored by TLC. The
workup procedure was identical to that described in the general
method A.
between H2O (50 mL) and CH2Cl2 (50 mL). After phase separation,
the aqueous phase was extracted again with CH2Cl2 (2 × 50 mL) and
the combined extracts were dried (Na2SO4) and concentrated. The
crude material was purified by flash chromatography on silica gel
(EtOAc in hexanes, 25–45%) to yield the azide 11 (706 mg, 75%)
as a colorless oil; [a]D20 –57.71 (c = 0.7833, CHCl3).
IR (neat): 3014, 2098, 1733, 1631, 1370, 1230, 1025, 973, 905, 835
cm–1.
[(1R,2S,4S,5S)-2-Acetoxy-4-(3-(benzyloxymethyl)-5-methyl-
2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)bicyclo[3.1.0]hexan-
1-yl]methyl Acetate (9a) and ((1R,2S,4S,5S)-2-Acetoxy-4-[1-
(benzyloxymethyl)-5-methyl-6-oxo-1,6-dihydropyrimidin-2-
yloxy)bicyclo[3.1.0]hexan-1-yl]methyl Acetate (9b)
The reaction was carried out according to the general coupling pro-
cedure, Method B, with 3-N-BOM-thymine tetramethylammonium
salt (126 mg, 0.393 mmol), mesylate 8 (40.0 mg, 0.131 mmol), mo-
lecular sieves (4 Å, 40 mg), and DMF (2.0 mL). The mixture was
stirred overnight at r.t..
1H NMR (CDCl3, 400 MHz): d = 5.49 (dd, J = 8.4, 8.4 Hz, 1 H, H-
2), 4.22 (d, J = 12.0 Hz, 1 H, CHHOAc), 3.97 (d, J = 12.0 Hz, 1 H,
CHHOAc), 3.81(d, J = 6.2 Hz, 1 H, H-4), 2.25 (ddd, J = 14.8, 8.1,
1.0 Hz, 1 H, H-3a), 2.09 (s, 3 H, OCOCH3), 1.99 (s, 3 H, OCOCH3),
1.53 (dd, J = 8.6, 4.3 Hz, 1 H, H-5), 1.41 (ddd, J = 14.8, 8.4, 6.2 Hz,
1 , H-3b), 0.84 (dd, J = 6.2, 4.3 Hz, 1 H, H-6a), 0.79–0.75 (m, 1 H,
H-6b).
13C NMR (CDCl3, 100 MHz): d = 171.04, 170.83 (2 × OCOCH3),
74.73 (C-2), 65.05 (CH2OAc), 61.51 (C-4), 34.53 (C-3), 30.78 (C-
1), 26.55 (C-5), 20.96, 20.79 (2 × OCOCH3), 11.06 (C-6).
N1-Alkylated Product 9a
Yield: 39.4 mg (66%).
FAB-MS: m/z (%) = 254 (45), 194 (100).
1H NMR (400 MHz, CDCl3): d = 7.35–7.20 (m, 6 H, CH-arom, H-
6), 5.53 (dd, J = 8.5, 8.5 Hz, 1 H, H-2¢), 5.47 (s, 2 H, OCH2N), 5.04
(d, J = 7.7 Hz, 1 H, H-4¢), 4.67 (s, 2 H, CH2-benzyl), 4.60 (d,
J = 12.0 Hz, 1 H, CHHOAc), 3.75 (d, J = 12.0 Hz, 1 H, CHHOAc),
2.21 (dd, J = 15.7, 8.5 Hz, 1 H, H-3¢a), 2.10 (s, 3 H, OCOCH3), 2.04
(s, 3 H, OCOCH3), 1.93 (d, J = 1.0 Hz, 3 H, CH3), 1.74 (ddd,
J = 15.7, 8.5, 8.5 Hz, 1 H, H-3¢b), 1.43 (dd, J = 8.8, 4.1 Hz, 1 H, H-
5¢), 0.97 (dd, J = 6.1, 4.1 Hz, 1 H, H-6¢a), 0.87 (dd, J = 8.8, 6.1 Hz,
1 H, H-6¢b).
13C NMR (100 MHz, CDCl3): d = 171.00, 170.53 (2 × OCOCH3),
163.16 (C-4), 151.35 (C-2), 138.03 (CH-arom), 135.06 (C-6),
128.22, 127.60, 127.58 (CH-arom), 110.28 (C-5), 73.68 (C-2¢),
72.25 (CH2-benzyl), 70.78 (OCH2N), 65.20 (CH2OAc), 56.55 (C-
4¢), 35.94 (C-1¢), 32.19 (C-3¢), 26.16 (C-5¢), 20.91 (2 × OCOCH3),
13.42 (CH3), 11.15 (C-6¢).
Anal. Calcd for C11H15N3O4: C, 52.17; H, 5.97; N, 16.59. Found: C,
52.26; H, 6.01; N, 16.35.
Method B: The mesylate 8 (81.0 mg, 0.236 mmol) was dissolved in
anhyd DMF (2.0 mL) and NaN3 (170 mg, 2.36 mmol) was added in
one portion under argon at r.t. The mixture was heated to 90 °C for
1 h and allowed to cool to r.t. The mixture was poured into a mixture
of phosphate buffer (pH 7.2, 25 mL) and Et2O (25 mL) and the
aqueous phase was extracted with Et2O (2 × 20 mL). The combined
organic extracts were dried (MgSO4) and concentrated. Flash chro-
matography on silica gel (EtOAc in hexanes, 25–45%) yielded the
azide 11 (43.6 mg, 73%) as a colorless oil. The spectroscopic data
were identical to those reported above.
[(1R,2S,4S,5S)-2-Acetoxy-4-aminobicyclo[3.1.0]hexan-1-
yl]methyl Acetate (12)
APCI-MS: m/z (%) = 457 (100), 397 (95).
The azide 11 (690 mg, 2.72 mmol) was dissolved in MeOH (25 mL)
and CH2Cl2 (25 mL) under argon at r.t. and Lindlar’s catalyst (100
mg) was added. The mixture was stirred overnight at r.t., until all the
starting material was consumed. The mixture was filtered over a
short pad of Celite and the solvent was evaporated off. The crude
amine 12 (618 mg, 100%) was sufficiently pure to be used in the
next step without any further purification. An analytical sample was
prepared by flash chromatography on silica gel (MeOH in EtOAc,
10–40%): [a]D20 –19.21 (c = 0.358, CHCl3).
O2-Alkylated Product 9b
Yield: 8.6 mg (15%).
1H NMR (400 MHz, CDCl3): d = 7.39 (q, J = 1.0 Hz, 1 H, H-6),
7.35–7.20 (m, 5 H, CH-arom), 5.60 (dd, J = 8.1, 8.1 Hz, 1 H, H-2¢),
5.53 (d, J = 9.8 Hz, 1 H, OCHHN), 5.47 (d, J = 9.8 Hz, 1 H,
OCHHN), 5.35 (d, J = 5.1 Hz, 1 H, H-4¢), 4.66 (s, 2 H, CH2-benzyl),
4.25 (d, J = 12.0 Hz, 1 H, CHHOAc), 3.96 (d, J = 12.0 Hz, 1 H,
CHHOAc), 2.45 (ddd, J = 15.4, 8.1, 1.1 Hz, 1 H, H-3¢a), 2.04 (s, 3
H, OCOCH3), 1.94 (d, J = 1.0 Hz, 3 H, CH3), 1.92 (s, 3 H,
OCOCH3), 1.74 (dd, J = 8.8, 4.3 Hz, 1 H, H-5¢), 1.57–1.51 (m, 1 H,
H-3¢b), 0.91 (dd, J = 6.2, 4.3 Hz, 1 H, H-6¢a), 0.83 (dd, J = 8.8, 6.2
Hz, 1 H, H-6¢b).
13C NMR (100 MHz, CDCl3): d = 170.94, 170.87 (2 × OCOCH3),
154.18 (C-2), 148.64 (C-4), 137.65, 128.32, 127.71, 127.49 (CH-
arom), 117.47 (C-5), 79.72 (C-4¢), 74.86 (C-2¢), 72.15 (CH2-ben-
zyl), 70.51 (OCH2N), 65.19 (CH2OAc), 34.52 (C-1¢), 30.69 (C-3¢),
26.68 (C-5¢), 20.98, 20.68 (2 × OCOCH3), 13.09 (CH3), 10.80 (C-
6).
IR (neat): 3332, 2947, 1729, 1654, 1548, 1370, 1238, 1025, 733
cm–1.
1H NMR (CDCl3, 400 MHz): d = 5.45 (dd, J = 8.4, 8.4 Hz, 1 H, H-
2), 4.17 (d, J = 11.6 Hz, 1 H, CHHOAc), 3.92 (d, J = 11.6 Hz, 1 H,
CHHOAc), 3.15 (d, J = 6.0 Hz, 1 H, H-4), 2.40–2.10 (br s, 2 H,
NH2), 1.94 (s, 3 H, OCOCH3), 1.92 (s, 3 H, OCOCH3), 1.74 (dd,
J = 13.5, 8.0 Hz, 1 H, H-3a), 1.30–1.22 (m, 2 H, H-3b, H-5), 0.72
(dd, J = 4.9, 4.9 Hz, 1 H, H-6a), 0.62 (dd, J = 8.2, 5.5 Hz, 1 H, H-
6b).
13C NMR (CDCl3, 100 MHz): d = 171.46, 171.45 (OCOCH3), 75.97
(C-2), 66.39 (CH2OAc), 51.15 (C-4), 36.24 (C-3), 30.18 (C-1),
29.53 (C-5), 19.53, 1936 (OCOCH3), 10.38 (C-6).
APCI-MS: m/z (%) = 457 (45), 211 (100).
FAB-MS: m/z (%) = 228 (100), 186 (38).
Formation of the Heterocycle by a Linear Approach
[(1R,2S,4S,5S)-2-Acetoxy-4-azidobicyclo[3.1.0]hexan-1-
yl]methyl Acetate (11)
Anal. Calcd for C11H17NO4·0.2 H2O: C, 57.23; H, 7.60; N, 6.07.
Found: C, 57.08; H, 7.59; N, 5.86.
Method A: To a stirred solution of the alcohol 2 (850 mg, 3.72
mmol) in anhyd DMF (25 mL) was added diphenylphosphoryl
azide (DPPA, 2.40 mL, 11.2 mmol) and Et3N (1.80 mL, 13.0 mmol)
under argon at r.t. The mixture was warmed to 60 °C and stirred for
20 h. The solvent was evaporated off and the residue was partitioned
((1¢R,2¢S,4¢S,5¢S)-2¢-Acetoxy-4¢-{3-[(E)-3-methoxy-2-methyl-
acryloyl]ureido}bicyclo[3.1.0]hexan-1¢-yl)methyl Acetate (14)
To a solution of dried AgNCO (198 mg, 1.32 mmol) in anhyd ben-
zene (5.0 mL) under argon was added 3-methoxy-2-methylacryloyl
Synthesis 2007, No. 22, 3451–3460 © Thieme Stuttgart · New York

PAPER
Optimizing the Synthesis of North-Methanocarbathymidine
Greenwich, 1996, 89. (g) Mitsuya, H. In Anti-HIV
3459
chloride dropwise at r.t. The mixture was heated to reflux for 1 h
and then cooled to r.t. again. The supernatant was added via syringe
to a stirred solution of the amine 12 (50 mg, 0.22 mmol) in anhyd
DMF (2.0 mL) at 0 °C under argon. The solution was allowed to
warm to r.t. and stirred for 3 h. The solvent was evaporated off and
the residue was purified by flash chromatography on silica gel
(EtOAc in hexanes, 50–75%) to yield the title compound 14 (68.9
mg, 85%) as a colorless foam; [a]D20 –21.6 (c = 0.25, CHCl3).
Nucleosides: Past, Present and Future; Landes: Texas,
1997. (h) Pan, S.; Amankulor, N. M.; Zhao, K. Tetrahedron
1998, 54, 6587. (i) Agrogoglio, L. A.; Challand, S. R. In
Acyclic, Carbocyclic and L-Nucleosides; Kluwer Academic
Publishers: Dordrecht, 1998. (j) Simons, C. In Nucleoside
Mimetics: Their Chemistry and Biological Properties;
Gordon and Breach Science Publishers: New York, 2001.
(3) Marquez, V. E.; Hughes, S. H.; Sei, S.; Agbaria, R. Antiviral
Res. 2006, 71, 268.
(4) (a) Rodriguez, J. B.; Marquez, V. E.; Nicklaus, M. C.;
Barchi, J. J. Jr. Tetrahedron Lett. 1993, 34, 6233.
(b) Altmann, K. H.; Kesselring, R.; Francotte, E.; Rihs, G.
Tetrahedron Lett. 1994, 35, 2331. (c) Rodriguez, J. B.;
Marquez, V. E.; Nicklaus, M. C.; Mitsuya, H.; Barchi, J. J.
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IR (neat): 3253, 2944, 1735, 1680, 1542, 1476, 1372, 1294, 1237,
1149, 1025, 986 cm–1.
1H NMR (CDCl3, 400 MHz): d = 8.87 – 8.80 (m, 1 H, NH), 7.90–
7.69 (m, 1 H, NH), 7.24–7.21 (m, 1 H, H-3), 5.49 (dd, J = 8.4, 8.4
Hz, 1 H, H-2¢), 4.28 (d, J = 11.8 Hz, 1 H, CHHOAc), 4.21 (dd,
J = 6.6, 6.6 Hz, 1 H, H-4¢), 3.87 (d, J = 11.8 Hz, 1 H, CHHOAc),
3.79 (d, J = 0.8 Hz, 3 H, 3-OCH3), 2.19 (dd, J = 14.4, 8.0 Hz, 1 H,
H-3¢a), 2.08 (s, 3 H, OCOCH3), 1.98 (s, 3 H, OCOCH3), 1.70 (d,
J = 1.0 Hz, 3 H, CH3), 1.43 (dd, J = 8.5, 4.8 Hz, 1 H, H-5¢), 1.43–
1.40 (m, 1 H, H-3¢b), 0.90 (dd, J = 6.0, 4.8 Hz, 1 H, H-6¢a), 0.73 (dd,
J = 8.5, 6.0 Hz, 1 H, H-6¢b).
13C NMR (CDCl3, 100 MHz): d = 170.32, 169.99 (2 × OCOCH3),
167.96 (C-1), 157.38 (C-3), 152.20 (C=O, urea), 105.96 (C-2),
73.75 (C-2¢), 64.36 (CH2OAc), 60.52 (3-OCH3), 49.41 (C-4¢), 34.10
(C-3¢), 29.65 (C-1¢), 26.27 (C-5¢), 20.06, 19.82 (2 × OCOCH3),
10.09 (2-CH3), 7.78 (C-6¢).
(5) Altona, C.; Sundaralingam, M. J. Am. Chem. Soc. 1972, 94,
8205.
(6) (a) Marquez, V. E.; Ezzitouni, A.; Russ, P.; Siddiqui, M. A.;
Ford, H.; Feldman, R. J.; Mitsuja, H.; George, C.; Barchi, J.
J. J. Am. Chem. Soc. 1998, 120, 2780. (b) Marquez, V. E.;
Russ, P.; Alonso, R.; Siddiqui, M. A.; Hernandez, S.;
George, C.; Nicklaus, M. C.; Dai, F.; Ford, H. Helv. Chim.
Acta 1999, 82, 2119. (c) Kim, H. S.; Ravi, R. G.; Marquez,
V. E.; Maddileti, S.; Wihlborg, A.-K.; Erlinge, D.; Malmsjö,
M.; Boyer, J. L.; Harden, T. K.; Jacobson, K. A. J. Med.
Chem. 2002, 45, 208. (d) Marquez, V. E.; Ben-Kasus, T.;
Barchi, J. J.; Green, K. M.; Nicklaus, M. C.; Agbaria, R. J.
Am. Chem. Soc. 2004, 126, 543. (e) Marquez, V. E.; Choi,
Y.; Comin, M. J.; Russ, P.; George, C.; Huleihel, M.; Ben-
Kasus, T.; Agbaria, R. J. Am. Chem. Soc. 2005, 127, 15145.
(f) Comin, M. J.; Agbaria, R.; Ben-Kasus, T.; Huleihel, M.;
Liao, C.; Sun, G.; Nicklaus, M. C.; Deschamps, J. R.;
Parrish, D. A.; Marquez, V. E. J. Am. Chem. Soc. 2007, 129,
6216.
FAB-MS: m/z (%) = 369 (27), 309 (45), 99 (100).
Anal. Calcd for C17H24N2O7·0.1 H2O: C, 55.16; H, 6.59; N, 7.57.
Found: C, 54.80; H, 6.51; N, 7.49.
1-[(1¢S,2¢S,4¢S,5¢R)-4¢-Hydroxy-5¢-(hydroxymethyl)bicy-
clo[3.1.0]hexan-2¢-yl)-5-methylpyrimidine-2,4(1H,3H)-dione
(N-MCT, 1)
The urea 14 (50 mg, 0.136 mmol) was dissolved in EtOH (3.0 mL)
and aq 2 N HCl (0.3 mL) was added. The mixture was heated to re-
flux and stirred overnight. The solvent was removed under reduced
pressure and the residue was purified by chromatography on a
Chromatotron (MeOH in CH2Cl2, 5–15%) to yield N-MCT (1; 30.5
mg, 89%) as a colorless foam. The spectroscopic data were identical
to those reported above.
(7) (a) Marquez, V. E.; Siddiqui, M. A.; Ezzitouni, A.; Russ, P.;
Wang, J.; Wagner, R. W.; Matteucci, M. D. J. Med. Chem.
1996, 39, 3739. (b) Ezzitouni, A.; Marquez, V. E. J. Chem.
Soc., Perkin Trans. 1 1997, 1073. (c) Russ, P.;Schelling, P.;
Scapozza, L.; Folkers, G.; De Clercq, E.; Marquez, V. E. J.
Med. Chem. 2003, 46, 5045.
(8) (a) Zalah, L.; Huleihel, M.; Manor, E.; Konson, A.; Ford, H.
Jr.; Marquez, V. E.; Johns, D. G.; Agbaria, R. Antiviral Res.
2002, 55, 63. (b) Huleihel, M.; Talishanisky, M.; Ford, H.
Jr.; Marquez, V. E.; Kelley, J. A.; Johns, D. G.; Agbaria, R.
Int. J. Antimicrob. Agents 2005, 25, 427.
(9) Zhu, W.; Burnett, A.; Dorjsuren, D.; Roberts, P. E.;
Huleihel, M.; Shoemaker, R. H.; Marquez, V. E.; Agbaria,
R.; Sei, S. Antimicrob. Agents Chemother. 2005, 49, 4965.
(10) Boyer, P. L.; Julias, J. G.; Marquez, V. E.; Hughes, S. H. J.
Mol. Biol. 2005, 345, 441.
(11) (a) Moon, H. R.; Ford, H. Jr.; Marquez, V. E. Org. Lett.
2000, 2, 3793. (b) Yoshimura, Y.; Moon, H. R.; Choi, Y.;
Marquez, V. E. J. Org. Chem. 2002, 67, 5938.
(12) Cruickshank, K. A.; Jiricny, J.; Reese, C. B. Tetrahedron
Lett. 1984, 25, 681.
Acknowledgment
This research was supported with funds from the Intramural
Research Program of the NIH, Center for Cancer Research, NCI
Frederick.
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