Stereoselective Synthesis of 1′,2′- cis -Disubstituted Carbocyclic ribo -Nucleoside Analogues

Article abstract of DOI:10.1055/s-0036-1591732

Herein we disclose an efficient strategy for the convergent synthesis of 1′,2′- cis -disubstituted carbocyclic ribo -nucleoside analogues. Starting from an enantiomerically pure cyclopentenol precursor, the key step for the preparation of the highly functionalized carbocyclic building block is an asymmetric dihydroxylation. Employing different variants of the Mitsunobu protocol, the condensation with all-natural nucleobases or their precursors affords a series of ribo -configured carbocyclic 1′,2′- cis -disubstituted nucleoside analogues.

Full text of DOI:10.1055/s-0036-1591732

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–K
paper
A
en
S. Weising et al.
Paper
Synthesis
Stereoselective Synthesis of 1′,2′-cis-Disubstituted Carbocyclic
ribo-Nucleoside Analogues
Simon Weisinga
Ilaria Torquatia,b
Chris Meier*a
OH
B
OH
4 steps
66%
3 steps
BnO
HO
BnO
O
O
HO
OH
a Organische Chemie, Fakultät für Mathematik, Informatik und Natur-
wissenschaften, Universität Hamburg, Martin-Luther-King-Platz 6,
20146 Hamburg, Germany
B = thymine (14%)
B = uracil (11%)
B = cytosine (11%)
B = adenine (38%)
B = guanine (23%)
chris.meier@chemie.uni-hamburg.de
b School of Pharmacy, Medicinal Chemistry Unit, University of Camerino,
via S. Agostino 1, 62032 Camerino, Italy
Received: 15.10.2017
Accepted after revision: 03.11.2017
Published online: 20.12.2017
carba-dT (3) in wild-type HIV-1 and in two multidrug-re-
sistant HIV-1 clones (E2-2 and 8ka3).7 Besides its promising
potency against the wild-type HIV-1 strain, carba-dT has
shown an increased antiviral effect against the mutant
strains. Moreover, we recently showed that the antiviral ac-
tivity of carba-dT could be increased by 15-fold (wild-type
HIV-1) by application of our TriPPPro-approach.8
DOI: 10.1055/s-0036-1591732; Art ID: ss-2017-n0517-op
Abstract Herein we disclose an efficient strategy for the convergent
synthesis of 1′,2′-cis-disubstituted carbocyclic ribo-nucleoside ana-
logues. Starting from an enantiomerically pure cyclopentenol precur-
sor, the key step for the preparation of the highly functionalized carbo-
cyclic building block is an asymmetric dihydroxylation. Employing
different variants of the Mitsunobu protocol, the condensation with all-
natural nucleobases or their precursors affords a series of ribo-config-
ured carbocyclic 1′,2′-cis-disubstituted nucleoside analogues.
O
NH
N
N
N
N
NH
N
HO
HO
Key words stereoselective synthesis, carbocyclic nucleosides, asym-
N
NH2
N
NH2
metric dihydroxylation, Mitsunobu reaction, heterocycles
OH
1
2
Over recent decades the development of new nucleo-
side analogues has become one of the cornerstones of anti-
viral chemotherapy. Carbocyclic nucleosides, composed of a
cyclopentane ring instead of the ribose ring of natural nu-
cleosides, constitute an important class of these analogues.
The small but significant difference in their chemical struc-
ture has led to several advantages compared to the natural
nucleosides bearing the ring oxygen atom, e.g., hydrolytic
stability and thus higher bioavailability.1 Moreover, the dif-
ference in the conformation of the cyclopentane ring in car-
bocyclic nucleosides compared to their natural counter-
parts plays an important role in their biological activity.2
Since the development of this class of nucleoside ana-
logues was started, several of these compounds have been
found to exhibit promising antiviral activities.2,3 Further
modifications of the five-membered carbocycle and/or nu-
cleobase led to a variety of highly antivirally active carbocy-
clic nucleosides.4 Prominent examples are abacavir5 (1) and
entecavir6 (2) (Figure 1), which are potent inhibitors of HIV
and HBV, respectively, and were approved by the FDA for
medical use in the United States in 1998 and 2005, respec-
tively. Recently, we reported on the antiviral activity of
O
N
O
N
O
I
NH
NH
NH
O
O
HO
N
O
HO
HO
OH
OH
4
3
5
Figure 1 Antiviral active carbocyclic nucleosides
In 2006, carba-iso-dT (4) (a 1′,2′-cis-disubstituted ana-
logue) was reported to have moderate antiviral activity
(EC50 value: 10 μM; HIV-1) without causing cytotoxicity
(CC50 value: >250 μM).9 In line with this, a few years earlier,
Santana et al. reported that the racemic iodouracil deriva-
tive (±)-5 showed moderate anti-HIV activity (EC50 value:
10 μg/mL; HIV-1) as well.10 These promising data motivated
us to develop an efficient, stereoselective, and convergent
synthesis for 1′,2′-cis-disubstituted carbocyclic ribo-nucle-
oside analogues. With this strategy (Scheme 1), we suc-
ceeded in preparing a series of these compounds that were
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

B
S. Weising et al.
Paper
Synthesis
OH
OAc
OAc
Na
OH
a
OAc
ref. 11
b
c
d
BnO
BnO
BnO
90%
85%
90%
96%
BnO
BnO
O
O
O
O
HO
OH
6
7
8
9
10
11
Scheme 1 Reagents and conditions: (a) pyridine, acetic anhydride, r.t., overnight; (b) AD-mix-β, MeSO2NH2, t-BuOH/H2O (2:1), 0 °C, 48h; (c) 2,2-dime-
thoxypropane, p-TsOH·H2O, acetone, r.t., overnight; (d) NaOH (1%) in methanol, r.t., overnight.
previously difficult to access. This now sets the basis for an
analysis regarding the biological activity profiles of these
compounds.
with sodium hydroxide in methanol worked in nearly quan-
titative yield (96%) and gave key intermediate 11 in an over-
all yield of 66% starting from (1R,2S)-2-(benzyloxymeth-
yl)cyclopent-3-enol (7).
The synthesis of carbocyclic nucleoside analogues is
challenging due to the introduction of multiple stereogenic
centers. Since we aimed to develop a synthetic route that
would originate from readily available cyclopentadiene, we
chose (1R,2S)-2-(benzyloxymethyl)-cyclopent-3-enol (7) as
the starting point for the synthesis of key intermediate 11.
Cyclopentenol 7 was first described by Biggadike et al. in
the synthesis of carbocyclic nucleosides.11 The alkylation of
sodium cyclopentadiene with benzyl chloromethyl ether
and the subsequent stereoselective hydroboration with the
appropriate enantiomerically pure diisopinocampheylbo-
rane led to the corresponding (+)- or (–)-enantiomer with
high enantioselectivities (>97% ee). The yields for this one-
pot procedure, however, proved unreliable in our hands,
varying between 23–65%. Finally, by using commercially
available sodium cyclopentadienylide, the reaction was
performed in reproducible and good yields (>65%, >97%
ee).6a,11
In contrast to earlier work, the resulting hydroxy group
was not mesylated (for subsequent elimination reaction),
but acetylated for temporary protection.12 This step was
crucial because the acetyl group is easier to remove under
milder conditions compared to the mesylate.13 The stan-
dard protocol using an excess of acetic anhydride in pyri-
dine led to the desired acetate 8 in almost quantitative
yield. Next, protected cyclopentene 8 was dihydroxylated in
an asymmetric dihydroxylation reaction using commercial
AD-mix-α or AD-mix-β in the presence of methanesulfon-
amide.12,14 The reactions were carried out at low tempera-
ture to achieve a good selectivity. AD-mix-α led to a diaste-
reomeric ratio of 3:1 and a yield of 62% for the desired diol
9, which is well in accordance with the reported mesylate
(3:1, 67%).12 The relative configuration of the two diastereo-
isomers was determined by NOE experiments. AD-mix-β
provided the two diastereomers in a diastereomeric ratio of
6:1, which is less selective compared to the mesylate (dias-
tereomeric ratio 11:1), although the yield of 85% for the
formed diol is comparable.12 The introduction of the isopro-
pylidene protecting group by reacting compound 9 with
2,2-dimethoxypropane and a catalytic amount of p-tolue-
nesulfonic acid in acetone yielded 10 as expected in high
yield (90%). The subsequent cleavage of the acetyl ester
The key step of our convergent strategy for synthesizing
a series of 1′,2′-cis-disubstituted carbocyclic ribo-nucleo-
side analogues was the Mitsunobu coupling of different nu-
cleobases or their precursors with cyclopentanol 11 (Table
1). First, the earlier reported protocol for the Mitsunobu re-
action with N3-benzoylpyrimidines was applied (entry 1).15
Therefore the DIAD–PPh3 complex is formed and added to a
solution of cyclopentanol 11 and the protected thymine at
–40 °C and subsequently warmed slowly to room tempera-
ture. Unfortunately, the reaction did not lead to full conver-
sion in this study and moreover, an elimination reaction led
to the formation of 17 as the major product. Additionally,
the N1/O2-alkylation ratio was almost 1:1. As is often re-
ported, the use of MeCN as the solvent should lead to the
preferred formation of the N-alkylated product. However,
this was unfortunately not the case here and we reasoned
that the low N1/O2-ratio might be due to less steric hin-
drance in the O2-alkylated product. Due to the poor forma-
tion of the desired product, the excess of Mitsunobu re-
agents and the low selectivity regarding N1- and O2-alkylat-
ed products, the purification of these compounds gave only
unsatisfying results. In an attempt to overcome this severe
limitation, the solvent was changed from MeCN to THF (Ta-
ble 1, entry 2). Now the reaction time was significantly re-
duced (a few hours instead of days), but in this case, the O2-
alkylated product was predominantly formed (ratio around
1:4, NMR analysis). Consequently, the use of MeCN as the
solvent in these reactions using N3-benzoylthymine led to
an increased elimination side reaction to yield product 17,
however, the alkylation ratio was strongly favorable as op-
posed to THF as the solvent. This was unexpected since a
previous report showed no strong effect on the N1/O2-al-
kylation ratio. However, the previous study was performed
on an unsubstituted cyclopentanol.15b An alternative way to
increase the rates of Mitsunobu reactions found in previous
literature involves microwave assistance.16 Thus, cyclopen-
tanol precursor 11 was treated with PPh3 (1.5 equiv), DIAD
(1.5 equiv) and N3-benzoyluracil (1.5 equiv) in MeCN at
50 °C (irradiation at 100 W) until full conversion of the cy-
clopentanol. On applying microwave irradiation the reac-
tion time was reduced to a maximum of 3 hours (gram
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

C
S. Weising et al.
Paper
Synthesis
scale), and since lower amounts of Mitsunobu reagents
were needed, the isolation of the desired product by col-
umn chromatography was much more efficient. However,
the N1/O2-ratio of the coupled product was still almost 1:1.
The identification of the N-alkylated on the O-alkylated
product was done by 13C NMR: in the case of the N-alkylat-
ed product the C–N carbon atom resonated at a chemical
shift of approximately 50–60 ppm, whereas in the O-al-
kylated product its resonance signal typically had a chemi-
cal shift of approximately 70–80 ppm. Moreover, the H-1′
protons were shifted downfield compared to those in the
N-alkylated counterpart.17 In this way, the thymine (12a)
and uracil (13a) compounds were obtained in only 20% and
15% yields, respectively. A direct condensation of cyclopen-
tanol 11 and N4-acetylcytosine was impossible due to the
selective formation of the O2-product 14b. This problem is
often described for cytosine derivatives using the Mitsuno-
bu reaction.17,18
followed by addition of concentrated aqueous ammonium
hydroxide solution gave the cytosine compound 14a in 84%
yield (Scheme 2).
O
NH2
NH
N
N
O
N
O
a
84%
BnO
BnO
O
O
O
O
13a
14a
Scheme 2 Reagents and conditions: (a) (i) 1H-1,2,4-triazole, POCl3,
Et3N, MeCN, 0 °C then r.t., 16 h; (ii) aq NH4OH (25%), r.t., 48 h.
The purine derivatives were prepared using the same
Mitsunobu protocol as that employed for the pyrimidines
uracil and thymine (Table 1, entries 6–8). However, in con-
trast to the pyrimidines, THF was used as the solvent be-
cause the use of MeCN and 6-chloropurine led to the 6-
chloropurine derivative 15 in a yield of only 49% and an in-
creased amount of the elimination side product 17. 6-Chlo-
ropurine and 2-amino-6-chloropurine can act as ambident
nucleophiles (N7/N9), but in both cases, only the N9-iso-
mers were isolated in 80% (15) and 70% (16) yields, respec-
tively. This might explain the moderate yields in the case of
the pyrimidines. The 6-chloropurine derivative 15 was
treated with 7 M ammonia in methanol in a closed micro-
wave reactor to give 18 in 78% yield. The reaction of 2-ami-
no-6-chloropurine 16 with sodium hydroxide in water led
to the guanine derivative 19 in a good yield of 65% (Scheme
3).
Table 1 Microwave-Assisted Mitsunobu Coupling of Nucleobases
nucleobase (1.5 equiv)
PPh3 (1.5 equiv)
OH
B
DIAD (1.5 equiv), solvent
100 W, 45 °C
BnO
BnO
BnO
O
O
O
O
O
O
11
for pyrimidines:
12–16
17
R'
N
R
R
R = Me, R' = OH 12
R = H, R' = OH 13
R = H, R' = NH2 14
N
N
O
O
N
R'
O2-alkylation b
N1-alkylation a
R1
Cl
Entry Nucleobase
Methoda
(solvent)
N1/O2
ratio
Product
(yield)
N
N
N
N
N
N
1
2
3
4
5
6
7
8
N3-benzoylthymine
N3-benzoylthymine
N3-benzoylthymine
N3-benzoyluracil
A (MeCN)
A (THF)
(1:1)
(1:4)
(1:1)
(1:1)
(0:1)
12a (18%)c
12a (13%)c
12a (20%)c
13a (15%)c
14a (–)c,d
N
R
N
R
a or b
BnO
BnO
B (MeCN)
B (MeCN)
B (MeCN)
B (MeCN)
B (THF)
O
O
O
O
N4-acetylcytosine
6-chloropurine
R = H, R1 = NH2 18 (78%)
R = NH2, R1 = OH 19 (65%)
R = H 15
R = NH2 16
(n.a.)b
(n.a.)b
(n.a.)b
15 (49%)
15 (80%)
16 (70%)
6-chloropurine
Scheme 3 Reagents and conditions: for R = H (a) 7 M NH3 in MeOH, mi-
crowave (50 W), 80 °C, 1 h; for R = NH2 (b) 0.5 M aq NaOH, reflux, 6 h.
2-amino-6-chloropurine
B (THF)
a Method A: PPh3 (3.0 equiv), DIAD (2.8 equiv), nucleobase (1.5 equiv), sol-
vent, –40 °C to r.t. Method B: as depicted in the scheme.
b n.a. not available.
Finally, the desired 1′,2′-cis-disubstituted carbocyclic
ribo-nucleoside analogues 25–29 were obtained in satisfy-
ing yields after cleavage of the isopropylidene group (78–
94%) by using acetic acid in water at 50 °C and subsequent
hydrogenolysis of the benzyl ether or Lewis acid induced
ether cleavage (56–94%) (Table 2).
c Pyrimidines were deprotected (1% NaOH in MeOH, r.t.) directly after Mit-
sunobu coupling.
d Only O2-alkylated 14b (70%) was observed.
Therefore, the cytidine derivative 14a was prepared
starting from the uracil derivative 13a: The treatment of
13a with 1H-1,2,4-triazole and POCl3 in anhydrous MeCN,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

D
S. Weising et al.
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Synthesis
Table 2 Deprotection Steps to ribo-Compounds 25–29
B
B
B
b–d
a
BnO
HO
BnO
O
O
HO
OH
HO
OH
12a–14a, 18, 19
20–24
25–29
(a) acetic acid/water (3:1), 50 °C; (b) Pd/C (10%), H2, MeOH, r.t.;
(c) TMS-iodine, CH2Cl2, r.t.; (d) Pd(OH)2/C (20%), MeOH,
cyclohexene, reflux.
Entry Substrate (B)
Product (yield)
Method
Product (yield)
1
2
3
4
5
6
7
8
12a (thymine)
13a (uracil)
20 (77%)
21 (78%)
(b)
(b)
(c)
(b)
(c)
(d)
(b)
(b)
25 (94%)
26 (91%)a
26 (91%)
27 (98%)a
27 (73%)b
27 (91%)
28 (73%)
29 (56%)
14a (cytosine)
22 (93%)
Figure 2 X-ray crystal structure of 25
18 (adenine)
19 (guanine)
23 (94%)
24 (90%)
ety of these nucleoside analogues became available. The
evaluation of the antiviral activity of these carbocyclic 1′,2′-
cis-disubstituted ribo-nucleoside analogues is currently un-
der investigation.
a Hydrogenolysis of the nucleobase led to an inseparable mixture or to com-
plete reduction.
b The reaction gave an inseparable mixture of two compounds with a ratio of
2:1.
With regard to the uracil (21) and cytosine (22) deriva-
tives, hydrogenolysis with a palladium catalyst and molec-
ular hydrogen led to an inseparable mixture of two com-
pounds, of which the minor compound was supposedly
formed by reduction of the pyrimidine base.19 One possibil-
ity to avoid this known problem for uracil and cytosine
All experiments involving water- or air-sensitive compounds were
carried out under anhydrous conditions (N2 atmosphere). Reagents
were purchased from various suppliers and used without further pu-
rification, unless otherwise noted. Anhydrous solvents were pur-
chased from Acros Organics (extra dry over molecular sieves) or dried
using an MBraun (MB SPS-800) System. Solvents for chromatography
were purchased as technical grade and distilled prior to use. Ultra-
pure water and MeCN for reverse-phase chromatography were puri-
fied with a Sartorius Aurium pro apparatus (Sartopore 0.2 μm, UV)
and purchased from VWR (HPLC grade), respectively. Column chro-
matography was performed on Macherey Nagel silica gel MN 60 M
(0.04–0.063 mm). Thin-layer chromatography was performed on pre-
coated TLC sheets ALUGRAM® Xtra SIL G/UV254 purchased from
Macherey Nagel. Visualization of non-UV active compounds was ac-
complished with vanillin in sulfuric acid, acetic acid and methanol.
Automated flash reverse-phase chromatography was performed by
using MN RS 16 C18 ec, RS 40 C18 ec or RS 120 C18 ec columns on an
Interchim Puriflash 430 system. Microwave reactions were carried
out in a CEM discover system in open- or closed-vessel mode at differ-
ent temperatures and power. Melting points were recorded using a
Electrothermal IA9200 apparatus. The optical rotations were mea-
sured with a P8000 polarimeter (A. Krüss Optonic GmbH) at the tem-
peratures indicated. NMR solvents were purchased from Euroiso-Top
(CDCl3, CD3OD and D2O) and Deutero (DMSO-d6). NMR spectra were
recorded at room temperature on Bruker Avance 300, Avance I 400,
DRX 500 and Avance III 600 instruments. IR and mass spectra were
recorded on a Bruker Alpha IR spectrophotometer and an Agilent
6224 ESI-TOF instrument, respectively. The determination of enantio-
meric excess was performed on a VWR-Hitachi System (L-2000,
L-2200, L-2455) with a ReproSil chiral OM column [250 × 4.6 mm,
5 μm; cellulose-tris-(3,5-dimethylphenyl)carbamate bound to SiO2
19
compounds is the use of Lewis acids (e.g., BX3 with
X = halide, TMS-iodide,20,21 etc.) for the benzyl ether cleav-
age instead of hydrogenolysis. Therefore, the uracil (21) and
cytosine (22) derivatives were treated with TMS-iodide in
dichloromethane, and in the case of 21 the desired ribo-
compound 26 was obtained in 91% yield. In the case of 22, a
mixture of two inseparable compounds was formed. In this
case the use of Pearlman’s catalyst and cyclohexene as the
hydrogen source led to the ribo-compound 27 in 91% yield.
The X-ray crystal structure analysis (Figure 2) of the
corresponding ribo-thymine derivative 25 unambiguously
proved the 1′,2′-cis-configured substitution pattern of the
five-membered carbocycle and the ribo-configuration of
the diol, as found in natural ribo-nucleosides. The confor-
mation of the ring carbons bearing the hydroxy functions is
3′-endo-4′-exo and shows similarities to the 3′-endo-2′-exo
twist conformation of natural ribo-nucleosides. The orien-
tation of the C2′–C6′ bond showed a gauche,trans confor-
mation.22
In conclusion, we have synthesized a new series of car-
bocyclic 1′,2′-cis-disubstituted ribo-nucleoside analogues.
By employing this short and reliable synthetic route, a vari-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

E
S. Weising et al.
Paper
Synthesis
with 100 nm pore size] using n-hexane (HPLC grade from VWR)/iso-
propanol (for spectroscopy from Honeywell) 10% for 40 min with a
flow rate of 0.5 mL/min.
temperature overnight and after completion, the solvent was re-
moved under reduced pressure. The resulting residue was purified on
silica gel (PE/EtOAc, 3:1) to yield 10 (3.43 g, 90%) as a colorless oil.
Rf = 0.40 (PE/EtOAc, 3:1); [α]D28 –16.8 (c 0.25, CHCl3).
(1R,2S)-2-[(Benzyloxy)methyl]cyclopent-3-en-1-yl Acetate (8)
IR (film): 2982, 2934, 2859, 1731, 1454, 1366, 1246, 1206, 1157,
1085, 1039, 870, 736, 697, 514 cm–1
.
Alcohol 7 (6.85 g, 33.5 mmol) was dissolved in anhydrous pyridine
(35 mL) and acetic anhydride (12.7 mL, 134 mmol) was added. The
yellowish solution was stirred at room temperature overnight. All
volatiles were removed under reduced pressure. The residue was co-
evaporated three times with toluene and once with dichloromethane.
The crude product was purified on silica gel (PE/EtOAc, 7:1) to yield 8
(7.46 g, 90%) as a colorless oil.
1H NMR (500 MHz, CDCl3): δ = 7.36–7.26 (m, 5 H, H-Bn), 5.07–5.03
(m, 1 H, H-1), 4.72–4.67 (m, 1 H, H-4), 4.56 (dd, 2J = 6.1 Hz, 3J = 1.9 Hz,
1 H, H-3), 4.48 (s, 2 H, CH2Ph), 3.53–3.48 (m, 2 H, H-6), 2.50–2.45 (m,
1 H, H-2), 2.30–2.22 (m, 1 H, H-5a), 2.08–2.01 (m, 4 H, H-5b, CH3),
1.51 (s, 3 H, CH3-iPr), 1.30 (s, 3 H, CH3-iPr).
13C NMR (126 MHz, CDCl3): δ = 170.9 (Cq-Ac), 138.1 (Cq-Bn), 128.5
(2 × C-Bn), 127.8 (C-Bn), 127.6 (2 × C-Bn), 110.9 (Cq-iPr), 83.6 (C-3),
80.8 (C-4), 78.9 (C-1), 73.4 (CH2Ph), 69.8 (C-6), 52.2 (C-2), 38.8 (C-5),
27.0 (CH3-iPr), 24.5 (CH3-iPr), 21.4 (CH3).
Rf = 0.47 (PE/EtOAc, 6:1); [α]D28 –130.4 (c 0.25, CHCl3).
IR (film): 2853, 1731, 1361, 1307, 1239, 1095, 1026, 983, 732, 696,
635 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.36–7.27 (m, 5 H, H-Bn), 5.79–5.75
(m, 1 H, H-4), 5.72–5.69 (m, 1 H, H-3), 5.22–5.18 (m, 1 H, H-1), 4.52 (s,
2 H, CH2Ph), 3.50–3.42 (m, 2 H, H-6), 3.03–2.97 (m, 1 H, H-2), 2.88–
2.81 (m, 1 H, H-5a), 2.36–2.29 (m, 1 H, H-5b), 2.04 (s, 3 H, CH3).
13C NMR (126 MHz, CDCl3): δ = 171.1 (Cq-Ac), 138.5 (Cq-Bn), 130.2 (C-
3), 129.8 (C-4), 128.5 (2 × C-Bn), 127.7 (3 × C-Bn), 76.9 (C-1), 73.3
(CH2Ph), 71.3 (C-6), 52.9 (C-2), 39.6 (C-5), 21.4 (CH3).
HRMS (ESI+): m/z [M + Na]+ calcd for C18H24O5Na: 343.1516; found:
343.1524.
(1R,2R,3R,4S)-2-(Benzyloxymethyl)-3,4-(isopropylidenedioxy)cy-
clopentanol (11)
Acetate 10 was dissolved in methanol containing 1% sodium hydrox-
ide (100 mL) and stirred at room temperature overnight. The solution
was neutralized with 1 M aq hydrochloric acid and all volatiles were
removed under reduced pressure. The residue was dissolved in ethyl
acetate/water (100 mL, 1:1) and the aqueous phase was extracted
three times with ethyl acetate. The combined organic layers were
dried over Na2SO4 and concentrated in vacuo. Purification on silica gel
(PE/EtOAc, 1:1) afforded the alcohol 11 (2.87 g, 96%) as a colorless oil.
HRMS (ESI+): m/z [M + Na]+ calcd for C15H18O3Na: 269.1148; found:
269.1154.
(1R,2R,3R,4S)-2-[(Benzyloxy)methyl]-3,4-dihydroxycyclopentyl
Acetate (9)
Acetate 8 (3.49 g, 14.2 mmol) was dissolved in tert-butanol/water
(120 mL, 2:1). After the solution had been cooled to 0 °C, methanesul-
fonamide (1.35 g, 14.2 mmol) and AD-mix β (19.9 g) were added, fol-
lowed by stirring for 48 h at this temperature. The reaction mixture
was quenched by the addition of saturated aqueous NaHSO3 solution
(60 mL) and stirred for 1 h at room temperature. The aqueous phase
was extracted three times with ethyl acetate and the combined or-
ganic layers were dried over Na2SO4. Concentration in vacuo followed
by purification on silica gel (PE/EtOAc, 1:2; CH2Cl2/MeOH, 9:1) afford-
ed the diol 9 (3.39 g, 85%) as a colorless, highly viscous oil.
Rf = 0.35 (PE/EtOAc, 1:1); [α]D28 +9.6 (c 0.25, CHCl3).
IR (film): 3207, 2990, 2937, 2855, 1454, 1370, 1353, 1259, 1204,
1153, 1090, 1028, 865, 753, 737, 699 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.27 (m, 5 H, H-Bn), 4.71–4.66
(m, 1 H, H-4), 4.50–4.45 (m, 3 H, CH2Ph, H-3), 4.10–4.05 (m, 1 H, H-1),
3.48 (dd, 2J = 9.4 Hz, 3J = 5.6 Hz, 1 H, H-6a), 3.42 (dd, 2J = 9.4 Hz,
3J = 6.5 Hz, 1 H, H-6b), 2.49–2.43 (m, 1 H, H-2), 2.20–2.12 (m, 1 H, H-
5a), 2.09–2.02 (m, 1 H, H-5b), 1.51 (s, 3 H, CH3-iPr), 1.31 (s, 3 H, CH3-
iPr).
13C NMR (101 MHz, CDCl3): δ = 138.1 (Cq-Bn), 128.6 (2 × C-Bn), 127.9
(C-Bn), 127.7 (2 × C-Bn), 110.7 (Cq-iPr), 83.4 (C-3), 81.0 (C-4), 77.4 (C-
1), 73.4 (CH2Ph), 70.5 (C-6), 54.4 (C-2), 40.5 (C-5), 27.4 (CH3-iPr), 24.1
(CH3-iPr).
Rf = 0.43 (PE/EtOAc, 1:3); [α]D28 –30.8 (c 0.25, CHCl3).
IR (film): 3408, 2860, 1728, 1453, 1362, 1241, 1098, 1025, 905, 804,
736, 697, 608, 527, 459 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.40–7.27 (m, 5 H, H-Bn), 4.90–4.84
(m, 1 H, H-1), 4.58–4.49 (m, 2 H, CH2Ph), 4.12–4.07 (m, 1 H, H-4), 3.89
(dd, 2J = 8.7 Hz, 3J = 4.3 Hz, 1 H, H-3), 3.78 (dd, 2J = 9.0 Hz, 3J = 4.4 Hz, 1
HRMS (ESI+): m/z [M + Na]+ calcd for C16H22O4Na: 301.1410; found:
301.1416.
2
3
H, H-6a), 3.60 (dd, J = 9.0 Hz, J = 7.6 Hz, 1 H, H-6b), 2.49–2.40 (m, 1
H, H-2), 2.30 (ddd, 2J = 15.4 Hz, 3J = 8.5, 5.2 Hz, 1 H, H-5a), 2.04 (s, 3 H,
CH3), 1.82 (ddd, 2J = 15.4, 3J = 3.8, 2.3 Hz, 1 H, H-5b).
Coupling of Nucleobases; General Procedure
To a solution/suspension of the alcohol 11 (1 equiv), triphenylphos-
phine (1.5 equiv) and the appropriate nucleobase (1.5 equiv) in MeCN
was added diisopropylazodicarboxylate (DIAD) (1.5 equiv) dropwise.
The reaction mixture was irradiated at 45 °C (100 W) until full con-
version was achieved. The nucleobases were deprotected as follows.
Purines: The solvent was removed under reduced pressure and the
residue was purified as indicated. Pyrimidines: The solvent was re-
moved under reduced pressure and the resulting residue was dis-
solved in methanol containing 1% sodium hydroxide and stirred at
room temperature overnight. The reaction was neutralized with 1 M
hydrochloric acid and concentrated in vacuo. The crude product was
purified as indicated.
13C NMR (126 MHz, CDCl3): δ = 171.1 (Cq-Ac), 138.0 (Cq-Bn), 128.6
(2 × C-Bn), 128.0 (C-Bn), 127.8 (2 × C-Bn), 76.4 (C-3), 73.8 (C-1), 73.7
(CH2Ph), 71.9 (C-4), 70.7 (C-6), 49.6 (C-2), 37.8 (C-5), 21.3 (CH3).
HRMS (ESI+): m/z [M + Na]+ calcd for C15H20O5Na: 303.1203; found:
303.1208.
(1R,2R,3R,4S)-2-(Benzyloxymethyl)-3,4-(isopropylidenedioxy)cy-
clopentyl Acetate (10)
To a solution of 9 (3.32 g, 11.8 mmol) in acetone (100 mL) were added
2,2-dimethoxypropane (7.3 mL, 59 mmol) and p-toluenesulfonic acid
monohydrate (101 mg). The reaction mixture was stirred at room
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

F
S. Weising et al.
Paper
Synthesis
1′,2′-cis-(6′-O-Benzyl)-3′,4′-O-(isopropylidene)-carba-ribo-thymi-
dine [1-((3aR,4R,5S,6aS)-4-((Benzyloxy)methyl)-2,2-dimethyltet-
rahydro-4H-cyclopenta[d][1,3]dioxol-5-yl}-5-methylpyrimidine-
2,4(1H,3H)-dione] (12a) and 1′,2′-cis-(6′-O-Benzyl)-3′,4′-O-(isopro-
pylidene)-carba-ribo-O2-thymidine [2-(((3aR,4S,5S,6aS)-4-((Benzy-
loxy)methyl)-2,2-dimethyltetrahydro-4H-
carba-ribo-O2-uridine [2-(((3aR,4S,5S,6aS)-4-((Benzyloxy)methyl)-
2,2-dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-5-yl)oxy)py-
rimidin-4(3H)-one] (13b)
The reaction was carried out according to the general coupling proce-
dure with cyclopentanol 11 (562 mg, 2.02 mmol), triphenylphos-
phine (785 mg, 3.03 mmol), N3-benzoyluracil (655 mg, 3.03 mmol)
and diisopropylazodicarboxylate (0.601 μL, 3.03 mmol) in MeCN
(15 mL). Purification on silica gel (PE/acetone, 1:1; CH2Cl2/acetone,
2:1 + 5% triethylamine) afforded 13a and traces of 13b.
cyclopenta[d][1,3]dioxol-5-yl)oxy)-5-methylpyrimidin-4(3H)-one]
(12b)
The reaction was carried out according to the general coupling proce-
dure with cyclopentanol 11 (280 mg, 1.01 mmol), triphenylphos-
phine
(399 mg,
1.52 mmol),
N3-benzoylthymine
(350 mg,
13a
1.52 mmol) and diisopropylazodicarboxylate (301 μL, 1.52 mmol) in
acetonitrile (7.5 mL). Purification on silica gel (PE/EtOAc, 1:1; PE/ace-
tone, 2:1 to 1:2) afforded 12a and 12b.
Yield: 115 mg (15%); colorless resin; Rf = 0.75 (CH2Cl2/EtOAc, 1:3);
[α]D28 –170.4 (c 0.25, MeOH).
IR (film): 3216, 2969, 2947, 2857, 1712, 1685, 1670, 1369, 1262,
1208, 1031, 810, 755, 702 cm–1
.
12a
1H NMR (600 MHz, CDCl3): δ = 8.35 (br s, 1 H, NH), 7.39–7.22 (m, 6 H,
28
Yield: 76.4 mg (20%); colorless resin; Rf = 0.30 (PE/EtOAc, 1:1); [α]D
3
H-Bn, H-6), 5.49 (dd, J = 8.1 Hz, 2.2 Hz, 1 H, H-5), 5.13–5.06 (m, 1 H,
–128.8 (c 0.25, MeOH).
H-1′), 4.79–4.75 (m, 1 H, H-4′), 4.68–4.65 (m, 1 H, H-3′), 4.42 (d,
2J = 11.7 Hz, 1 H, CHHPh), 4.33 (d, 2J = 11.7 Hz, 1 H, CHHPh), 3.51 (dd,
2J = 10.1 Hz, 3J = 3.8 Hz, 1 H, H-6a′), 3.34 (dd, 2J = 10.1 Hz, 3J = 2.5 Hz, 1
H, H-6b′), 2.62–2.58 (m, 1 H, H-2′), 2.43–2.35 (m, 1 H, H-5a′), 2.10–
2.04 (m, 1 H, H-5b′), 1.49 (s, 3 H, CH3-iPr), 1.32 (s, 3 H, CH3-iPr).
13C NMR (151 MHz, CDCl3): δ = 162.9 (Cq-4), 151.0 (Cq-2), 142.3 (C-6),
137.3 (Cq-Bn), 128.8 (2 × C-Bn), 128.4 (C-Bn), 128.0 (2 × C-Bn), 110.0
(Cq-iPr), 101.1 (C-5), 83.0 (C-3′), 77.8 (C-4′), 74.0 (CH2Ph), 68.6 (C-6′),
56.6 (C-1′), 47.1 (C-2′), 35.8 (C-5′), 26.6 (CH3-iPr), 24.1 (CH3-iPr).
IR (film): 2985, 2932, 2875, 1681, 1653, 1455, 1372, 1262, 1208,
1124, 1032, 735, 726, 696 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.55 (s, 1 H, NH), 7.39–7.21 (m, 5 H, H-
Bn), 7.17 (s, 1 H, H-6), 5.12–5.05 (m, 1 H, H-1′), 4.80–4.76 (m, 1 H, H-
4′), 4.69–4.66 (m, 1 H, H-3′), 4.39 (d, 2J = 11.6 Hz, 1 H, CHHPh), 4.33 (d,
2J = 11.6 Hz, 1 H, CHHPh), 3.52 (dd, 2J = 10.1 Hz, 3J = 4.0 Hz, 1 H, H-6a′),
3.35 (dd, 2J = 10.1 Hz, 3J = 2.7 Hz, 1 H, H-6b′), 2.64–2.59 (m, 1 H, H-2′),
2.46–2.39 (m, 1 H, H-5a′), 2.11–2.05 (m, 1 H, H-5b′), 1.82 (s, 3 H, CH3),
1.50 (s, 3 H, CH3-iPr), 1.32 (s, 3 H, CH3-iPr).
13C NMR (151 MHz, CDCl3): δ = 163.7 (Cq-4), 151.2 (Cq-2), 138.5 (C-6),
137.5 (Cq-Bn), 128.7 (2 × C-Bn), 128.2 (C-Bn), 127.6 (2 × C-Bn), 110.0
(Cq-iPr), 109.5 (Cq-5), 83.1 (C-3′), 77.9 (C-4′), 73.9 (CH2Ph), 69.0 (C-6′),
56.7 (C-1′), 47.3 (C-2′), 35.8 (C-5′), 26.7 (CH3-iPr), 24.2 (CH3-iPr), 12.7
(CH3).
HRMS (ESI+): m/z [M + H]+ calcd for C20H25N2O5: 373.1685; found:
373.1757.
1′,2′-cis-(6′-O-Benzyl)-3′,4′-O-(isopropylidene)-carba-ribo-cyti-
dine [4-Amino-1-((3aR,4R,5S,6aS)-4-((Benzyloxy)methyl)-2,2-di-
methyltetrahydro-4H-cyclopenta[d][1,3]dioxol-5-yl)pyrimidin-
2(1H)-one] (14a)
HRMS (ESI+): m/z [M + H]+ calcd for C21H27N2O5: 387.1920; found:
387.1917.
To a solution of 1,2,4-triazole (184 mg, 2.66 mmol) in MeCN (3 mL)
was added freshly distilled POCl3 (53.2 μL, 569 μmol) dropwise at
0 °C. After stirring for 10 min, anhydrous triethylamine (352 μL,
2.54 mmol) was added and the resulting suspension was stirred for a
further 20 min. Next, the uracil derivative 13a (110 mg, 295 μmol)
dissolved in dichloromethane (3 mL) was added and the reaction was
stirred at room temperature until full conversion. The reaction mix-
ture was treated with 25% aqueous ammonium hydroxide solution
(10 mL) for 48 h at room temperature. After evaporation of all vola-
tiles, the residue was dissolved in dichloromethane/water (1:1)
(50 mL) and the aqueous phase extracted three times with dichloro-
methane (each 50 mL). The combined organic layers were dried over
Na2SO4. After evaporation of the solvent, the crude product was puri-
fied on silica gel using automated flash chromatography (CH2-
Cl2/MeOH, 98:2 to 85:15) to afford 14a (92.7 mg, 84%) as a colorless
solid.
12b
Yield: 98.5 mg (25%) (contains Mitsunobu reagents); yellowish resin;
Rf = 0.28 (PE/EtOAc, 1:1).
IR (film): 2980, 2931, 2859, 1655, 1606, 1574, 1371, 1295, 1207,
1102, 1036, 732, 696 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.60–7.55 (m, 1 H, H-6), 7.33–7.21 (m,
5 H, H-Bn), 5.63–5.55 (m, 1 H, H-1′), 4.74–4.68 (m, 1 H, H-4′), 4.64 (dd,
3J = 6.3 Hz, 3J = 2.6 Hz, 1 H, H-3′), 4.52–4.44 (m, 2 H, CH2Ph), 3.61 (dd,
2J = 9.6 Hz, 3J = 5.7 Hz, 1 H, H-6a′), 3.51 (dd, 2J = 9.6 Hz, 3J = 5.1 Hz, 1 H,
H-6b′), 2.72–2.66 (m, 1 H, H-2′), 2.31 (ddd, 2J = 14.0 Hz, 3J = 6.5 Hz,
3J = 2.0 Hz, 1 H, H-5a′), 2.23 (ddd, 2J = 14.0 Hz, 3J = 7.9 Hz, 3J = 6.3 Hz, 1
H, H-5b′), 1.95 (d, 4J = 1.2 Hz, 3 H, CH3), 1.49 (s, 3 H, CH3-iPr), 1.30 (s, 3
H, CH3-iPr).
13C NMR (126 MHz, CDCl3): δ = 165.5 (Cq-4), 155.2 (Cq-2), 151.3 (C-6),
138.2 (Cq-Bn), 128.4 (2 × C-Bn), 127.8 (3 × C-Bn), 117.5 (Cq-5), 110.6
(Cq-iPr), 82.3 (C-3′), 78.8 (C-1′), 78.0 (C-4′), 73.4 (CH2Ph), 67.1 (C-6′),
47.9 (C-2′), 37.8 (C-5′), 27.0 (CH3-iPr), 24.3 (CH3-iPr), 12.5 (CH3).
24
Mp 104–115 °C; Rf = 0.12 (CH2Cl2/MeOH, 95:5); [α]D –135 (c 0.10,
MeOH).
IR (neat): 3333, 3106, 2986, 2934, 1621, 1479, 1370, 1206, 1036, 789,
696 cm–1
.
HRMS (ESI+): m/z [M + H]+ calcd for C21H27N2O5: 387.1920; found:
387.1926.
1H NMR (600 MHz, CDCl3): δ = 7.38–7.28 (m, 4 H, H-Bn, H-6), 7.24–
3
7.20 (m, 2 H, H-Bn), 5.88 (d, J = 7.5 Hz, 1 H, H-5), 5.16–5.09 (m, 1 H,
H-1′), 4.79 (m, 1 H, H-4′), 4.68–4.65 (m, 1 H, H-3′), 4.36–4.29 (m, 2 H,
CH2Ph), 3.46 (dd, 2J = 10.0 Hz, 3J = 3.9 Hz, 1 H, H-6a′), 3.26 (dd,
2J = 10.0 Hz, 3J = 2.7 Hz, 1 H, H-6b′), 2.71–2.67 (m, 1 H, H-2′), 2.42–
2.36 (m, 1 H, H-5a′), 2.07–2.03 (m, 1 H, H-5b′), 1.49 (s, 3 H, CH3- iPr),
1.31 (s, 3 H, CH3- iPr).
1′,2′-cis-(6′-O-Benzyl)-3′,4′-O-(isopropylidene)-carba-ribo-uridine
[1-((3aR,4R,5S,6aS)-4-((Benzyloxy)methyl)-2,2-dimethyltetrahy-
dro-4H-cyclopenta[d][1,3]dioxol-5-yl)pyrimidine-2,4(1H,3H)-di-
one] (13a) and 1′,2′-cis-(6′-O-Benzyl)-3′,4′-O-(isopropylidene)-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

G
S. Weising et al.
Paper
Synthesis
13C NMR (151 MHz, CDCl3): δ = 164.2 (Cq-4), 155.8 (Cq-2), 143.6 (C-6),
137.5 (Cq-Bn), 128.7 (2 × C-Bn), 128.1 (C-Bn), 127.8 (2 × C-Bn), 109.9
(Cq-iPr), 94.1 (C-5), 83.2 (C-3′), 77.9 (C-4′), 73.8 (CH2Ph), 68.7 (C-6′),
57.5 (C-1′), 46.9 (C-2′), 35.7 (C-5′), 26.7 (CH3-iPr), 24.2 (CH3-iPr).
HRMS (ESI+): m/z [M + H]+ calcd for C20H26N3O4: 372.1918; found:
372.1923.
HRMS (ESI+): m/z [M + H]+ calcd for C21H24ClN4O3: 415.1537; found:
415.1547.
1′,2′-cis-(6′-O-Benzyl)-3′,4′-O-(isopropylidene)-carba-ribo-2-ami-
no-6-chloropurine [9-((3aR,4R,5S,6aS)-4-((Benzyloxy)methyl)-2,2-
dimethyltetrahydro-4H-cyclopenta[d][1,3]dioxol-5-yl)-6-chloro-
9H-purin-2-amine] (16)
1′,2′-cis-(6′-O-Benzyl)-3′,4′-O-(isopropylidene)-carba-ribo-O2-cyti-
dine [2-(((3aR,4S,5S,6aS)-4-((Benzyloxy)methyl)-2,2-dimethyltet-
rahydro-4H-cyclopenta[d][1,3]dioxol-5-yl)oxy)pyrimidin-4-
amine] (14b)
The reaction was carried out according to the general coupling proce-
dure with cyclopentanol 11 (400 mg, 1.44 mmol), triphenylphos-
phine (567 mg, 2.16 mmol), 2-amino-6-chloropurine (518 mg,
2.16 mmol) and diisopropylazodicarboxylate (428 μL, 2.16 μmol) in
acetonitrile (10 mL). Purification on silica gel (PE/EtOAc, 1:2) afforded
16 (431 mg, 70%) as a colorless foam.
The reaction was carried out according to the general coupling proce-
dure with cyclopentanol 11 (83.0 mg, 298 μmol), triphenylphosphine
(117 mg, 447 μmol), N4-acetylcytosine (68.5 mg, 447 μmol) and di-
isopropylazodicarboxylate (88.6 μL, 447 μmol) in acetonitrile (5 mL).
The residue was treated with sodium methoxide (1 M, 1 mL) and af-
terwards, neutralized with acetic acid. Purification on silica gel (CH2-
Cl2/MeOH, 95:5) afforded 14b (77.8 mg, 70%) as a colorless foam.
Rf = 0.50 (CH2Cl2/MeOH, 95:5); [α]D24 –73 (c 0.1, MeOH).
IR (neat): 3423, 3327, 3206, 2933, 1634, 1561, 1406, 1227, 1033, 912,
697 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.90 (s, 1 H, H-8), 7.38–7.19 (m, 5 H, H-
Bn), 5.46 (br s, 2 H, NH2), 5.23–5.13 (m, 1 H, H-1′), 4.86–4.80 (m, 1 H,
H-4′), 4.76–4.72 (m, 1 H, H-3′), 4.34 (d, 2J = 11.6 Hz, 1 H, CHHPh), 4.28
(d, 2J = 11.6 Hz, 1 H, CHHPh), 3.43 (dd, 2J = 10.1 Hz, 3J = 3.7 Hz, 1 H, H-
IR (neat): 3338, 3182, 2933, 2858, 1629, 1588, 1403, 1206, 1031, 810,
734, 697 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.00 (d, 3J = 5.7 Hz, 1 H, H-6), 7.35–7.20
(m, 5 H, H-Bn), 6.05 (d, 3J = 5.7 Hz, 1 H, H-5), 5.65–5.55 (m, 1 H, H-1′),
4.92 (br s, 2 H, NH2), 4.78–4.64 (m, 2 H, H-4′, H-3′), 4.51–4.43 (m, 2 H,
6a′), 3.01 (dd, J = 10.1 Hz, J = 2.9 Hz, 1 H, H-6b′), 2.81–2.68 (m, 2 H,
H-5a′, H-2′), 2.33–2.25 (m, 1 H, H-5b′), 1.56 (s, 3 H, CH3-iPr), 1.36 (s, 3
H, CH3-iPr).
2
3
CH2Ph), 3.66 (dd, 2J = 9.6 Hz, 3J = 6.1 Hz,
1 H, H-6a′), 3.56 (dd,
13C NMR (101 MHz, CDCl3): δ = 159.2 (Cq-6), 154.0 (Cq-4), 151.1 (C-2),
141.4 (C-8), 137.3 (Cq-Bn), 128.7 (2 × C-Bn), 128.2 (C-Bn), 127.7
(2 × C-Bn), 124.9 (Cq-5), 109.9 (Cq-iPr), 83.3 (C-3′), 78.0 (C-4′), 73.8
(CH2Ph), 68.3 (C-6′), 54.3 (C-1′), 47.6 (C-2′), 36.8 (C-5′), 26.6 (CH3-iPr),
23.9 (CH3-iPr).
HRMS (ESI+): m/z [M + H]+ calcd for C21H25ClN5O3: 430.1640; found:
430.1649.
2J = 9.6 Hz, 3J = 6.8 Hz, 1 H, H-6b′), 2.77–2.67 (m, 1 H, H-2′), 2.31–2.16
(m, 2 H, H-5′), 1.50 (s, 3 H, CH3-iPr), 1.31 (s, 3 H, CH3-iPr).
13C NMR (101 MHz, CDCl3): δ = 164.9 (Cq-4), 164.8 (Cq-2), 157.8 (C-6),
138.6 (Cq-Bn), 128.4 (2 × C-Bn), 127.6 (2 × C-Bn), 127.5 (C-Bn), 110.7
(Cq-iPr), 99.4 (C-5), 82.4 (C-3′), 78.2 (C-4′), 77.3 (C-1′), 73.3 (CH2Ph),
67.4 (C-6′), 48.2 (C-2′), 37.9 (C-5′), 27.0 (CH3-iPr), 24.4 (CH3-iPr).
HRMS (ESI+): m/z [M + H]+ calcd for C20H26N3O4: 372.1918; found:
372.1929.
1′,2′-cis-(6′-O-Benzyl)-3′,4′-O-(isopropylidene)-carba-ribo-adenos-
ine [9-((3aR,4R,5S,6aS)-4-((Benzyloxy)methyl)-2,2-dimethyltetra-
hydro-4H-cyclopenta[d][1,3]dioxol-5-yl)-9H-purin-6-amine] (18)
1′,2′-cis-(6′-O-Benzyl)-3′,4′-O-(isopropylidene)-carba-ribo-6-chlo-
ropurine [9-((3aR,4R,5S,6aS)-4-((Benzyloxy)methyl)-2,2-dimeth-
yltetrahydro-4H-cyclopenta[d][1,3]dioxol-5-yl)-6-chloro-9H-
purine] (15)
In a microwave vessel, compound 15 (214 mg, 516 mmol) was treated
with 7 M ammonia in methanol (8 mL) at 80 °C (50 W) for 1 h. All the
volatiles were removed under reduced pressure and the residue was
purified on silica gel (CH2Cl2/MeOH, 92:8). After freeze-drying
(MeCN/H2O, 1:1), product 18 (160 mg, 78%) was obtained as a color-
less resin.
The reaction was carried out according to the general coupling proce-
dure with cyclopentanol 11 (150 mg, 539 μmol), triphenylphosphine
(283 mg, 1.08 mmol), 6-chloropurine (167 mg, 1.08 mmol) and diiso-
propylazodicarboxylate (212 μL, 1.08 mmol) in acetonitrile (5 mL).
Purification on silica gel (PE/EtOAc, 3:1 to 1:1) afforded 15 (179 mg,
80%) as a colorless foam.
Rf = 0.33 (CH2Cl2/MeOH, 9:1); [α]D28 –92.4 (c 0.25, MeOH).
IR (neat): 3311, 3136, 2983, 2934, 2859, 1644, 1596, 1573, 1472,
1371, 1249, 1207, 1095, 1038, 729, 698 cm–1
.
Rf = 0.40 (PE/EtOAc, 1:1); [α]D28 –124.0 (c 0.25, MeOH).
1H NMR (500 MHz, CDCl3): δ = 8.36 (s, 1 H, H-2), 7.87 (s, 1 H, H-8),
7.38–7.20 (m, 5 H, H-Bn), 5.66 (s, 2 H, NH2), 5.38–5.30 (m, 1 H, H-1′),
4.88–4.84 (m, 1 H, H-4′), 4.80–4.75 (m, 1 H, H-3′), 4.35–4.24 (m, 2 H,
CH2Ph), 3.41 (dd, 2J = 10.0 Hz, 3J = 3.8 Hz, 1 H, H-6a), 3.00 (dd,
2J = 10.0 Hz, 3J = 3.0 Hz, 1 H, H-6b), 2.85–2.76 (m, 2 H, H-2, H-5a),
2.40–2.31 (m, 1 H, H-5b), 1.55 (s, 3 H, CH3-iPr), 1.35 (s, 3 H, CH3-iPr).
13C NMR (151 MHz, CDCl3): δ = 155.4 (Cq-6), 153.0 (C-2), 150.6 (Cq-4),
139.9 (C-8), 137.6 (Cq-Bn), 128.7 (2 × C-Bn), 128.1 (C-Bn), 127.7
(2 × C-Bn), 119.8 (Cq-5), 110.0 (Cq-iPr), 83.4 (C-3′), 78.2 (C-4′), 73.8
(CH2Ph), 68.5 (C-6′), 54.5 (C-1′), 48.2 (C-2′), 37.1 (C-5′), 26.7 (CH3-iPr),
24.0 (CH3-iPr).
IR (neat): 2933, 1588, 1558, 1373, 1203, 1037, 953, 730, 697, 636, 564
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.74 (s, 1 H, H-2), 8.23 (s, 1 H, H-8),
7.37–7.16 (m, 5 H, H-Bn), 5.47–5.37 (m, 1 H, H-1′), 4.91–4.85 (m, 1 H,
H-4′), 4.78–4.73 (m, 1 H, H-3′), 4.34–4.23 (m, 2 H, CH2Ph), 3.43 (dd,
2J = 10.2 Hz, 3J = 3.9 Hz, 1 H, H-6a), 2.96 (dd, 2J = 10.2 Hz, 3J = 2.8 Hz, 1
H, H-6b), 2.90–2.77 (m, 2 H, H-2, H-5a), 2.43–2.35 (m, 1 H, H-5b), 1.55
(s, 3 H, CH3-iPr), 1.36 (s, 3 H, CH3-iPr).
13C NMR (101 MHz, CDCl3): δ = 152.2 (Cq-4), 152.1 (C-2), 151.0 (Cq-6),
144.6 (C-8), 137.1 (Cq-Bn), 131.5 (Cq-5), 128.7 (2 × C-Bn), 128.2 (C-Bn),
127.7 (2 × C-Bn), 110.1 (Cq-iPr), 83.3 (C-3′), 78.0 (C-4′), 73.9 (CH2Ph),
68.3 (C-6′), 55.1 (C-1′), 48.1 (C-2′), 37.0 (C-5′), 26.7 (CH3-iPr), 24.0
(CH3-iPr).
HRMS (ESI+): m/z [M + H]+ calcd for C21H26N5O3: 396.1957; found:
396.2043.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

H
S. Weising et al.
Paper
Synthesis
1′,2′-cis-(6′-O-Benzyl)-3′,4′-O-(isopropylidene)-carba-ribo-guano-
sine [2-Amino-9-((3aR,4R,5S,6aS)-4-((Benzyloxy)methyl)-2,2-di-
methyltetrahydro-4H-cyclopenta[d][1,3]dioxol-5-yl)-1,9-dihydro-
6H-purin-6-one] (19)
1′,2′-cis-(6′-O-Benzyl)-carba-ribo-uridine [1-((1S,2R,3R,4S)-2-
((Benzyloxy)methyl)-3,4-dihydroxycyclopentyl)pyrimidine-
2,4(1H,3H)-dione] (21)
The reaction was carried out according to the general isopropylidene
deprotection procedure with 13a (79.8 mg, 214 μmol) and acetic ac-
id/water (8 mL). Purification on silica gel (CH2Cl2/MeOH, 9:1) and
freeze-drying (MeCN/H2O, 1:1) afforded 21 (54.9 mg, 78%) as a color-
less cotton-like solid.
The 2-amino-6-chloropurine derivative 16 (0.357 g, 0.830 mmol) was
suspended in 1 M aqueous sodium hydroxide (10 mL) and heated to
reflux for 6 h. After cooling to room temperature, the pH value was
set to 5.5 with acetic acid. The resulting precipitate was filtered and
purified on silica gel by automated flash chromatography (CH2-
Cl2/MeOH, 95:5 to 80:20) to afford 19 (0.223 g, 65%) as a colorless sol-
id.
Rf = 0.45 (CH2Cl2/MeOH, 9:1); [α]D28 –58 (c 0.25, MeOH).
IR (neat): 2964, 1697, 1652, 1473, 1274, 1092, 1077, 738, 434, 419,
398 cm–1
.
24
Mp 257–264 °C (dec.); Rf = 0.12 (CH2Cl2/MeOH, 95:5); [α]D –72 (c
1H NMR (400 MHz, DMSO-d6): δ = 11.01 (br s, 1 H, NH), 7.54 (d,
3J = 8.0 Hz, 1 H, H-6), 7.35–7.18 (m, 5 H, H-Bn), 5.40 (d, 3J = 8.0 Hz, 1
H, H-5), 5.08–4.99 (m, 1 H, H-1′), 4.84 (br s, 2 H, OH), 4.33–4.20 (m, 2
H, CH2Ph), 4.02–3.97 (m, 1 H, H-4′), 3.94–3.87 (m, 1 H, H-3′), 3.40–
3.28 (m, 2 H, H-6′), 2.39–2.29 (m, 1 H, H-2′), 2.11–2.01 (m, 1 H, H-5a′),
1.94–1.85 (m, 1 H, H-5b′).
13C NMR (101 MHz, DMSO-d6): δ = 164.6 (C-4), 152.4 (C-2), 143.9 (C-
6), 138.1 (Cq-Bn), 128.2 (2 × C-Bn), 127.4 (2 × C-Bn), 127.3 (C-Bn),
100.0 (C-5), 74.2 (C-3′), 72.3 (CH2Ph), 70.6 (C-4′), 68.1 (C-6′), 54.6 (C-
1′), 45.0 (C-2′), 35.1 (C-5′).
0.1, MeOH).
IR (neat): 3394, 3195, 2858, 2738, 1683, 1597, 1384, 1037, 673 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.57 (br s, 1 H, NH), 7.65 (s, 1 H,
H-8), 7.35–7.18 (m, 5 H, H-Bn), 6.48 (br s, 2 H, NH2), 4.93–4.82 (m, 1
H, H-1′), 4.78–4.73 (m, 1 H, H-4′), 4.67–4.62 (m, 1 H, H-3′), 4.33–4.24
(m, 2 H, CH2Ph), 3.17 (dd, 2J = 9.9 Hz, 3J = 4.7 Hz, 1 H, H-6a′), 3.06 (dd,
2J = 9.9 Hz, 3J = 6.0 Hz, 1 H, H-6b′), 2.70–2.59 (m, 2 H, H-2′, H-5a′),
2.21–2.12 (m, 1 H, H-5b′), 1.41 (s, 3 H, CH3-iPr), 1.26 (s, 3 H, CH3-iPr).
13C NMR (101 MHz, DMSO-d6): δ = 156.8 (C-6), 153.5 (C-2), 151.4 (C-
4), 137.9 (Cq-Bn), 135.8 (C-8), 128.2 (2 × C-Bn), 127.4 (C-Bn), 127.3
(2 × C-Bn), 116.8 (C-5), 108.7 (Cq-iPr), 82.0 (C-3′), 77.0 (C-4′), 72.4
(CH2Ph), 66.9 (C-6′), 53.1 (C-1′), 46.8 (C-2′), 35.2 (C-5′), 26.3 (CH3-iPr),
23.6 (CH3-iPr).
HRMS (ESI+): m/z [M + H]+ calcd for C17H21N2O5: 333.1405; found:
333.1446.
1′,2′-cis-(6′-O-Benzyl)-carba-ribo-cytidine [4-amino-1-
((1S,2R,3R,4S)-2-((Benzyloxy)methyl)-3,4-dihydroxycyclopen-
tyl)pyrimidin-2(1H)-one] (22)
HRMS (ESI+): m/z [M + H]+ calcd for C21H26N5O4: 412.1979; found:
412.1980.
The reaction was carried out according to the general isopropylidene
deprotection procedure with 14a (50.2 mg, 135 μmol) and acetic ac-
id/water (6 mL). The crude product was purified on RP-18 silica gel
with automated flash chromatography (MeCN/H2O, 1:99 to 100:0) to
yield 22 (41.6 mg, 93%) as a colorless solid.
Isopropylidene Deprotection; General Procedure
The isopropylidene-protected nucleosides were dissolved in acetic
acid/water (3:1) and heated to 50 °C until complete conversion. After
evaporation of the solvents, the residue was co-evaporated three
times with toluene and once with dichloromethane. The crude prod-
uct was purified as indicated.
Mp 93 °C; Rf = 0.38 (CH2Cl2/MeOH, 80:20); [α]D24 –88 (c 0.1, MeOH).
IR (neat): 3327, 3185, 2857, 1636, 1604, 1480, 1284, 1078, 1026, 788,
697 cm–1
.
1′,2′-cis-(6′-O-Benzyl)-carba-ribo-thymidine [1-((1S,2R,3R,4S)-2-
((Benzyloxy)methyl)-3,4-dihydroxycyclopentyl)-5-methylpyrimi-
dine-2,4(1H,3H)-dione] (20)
1H NMR (600 MHz, DMSO-d6): δ = 7.49 (d, 3J = 7.4 Hz, 1 H, H-6), 7.33–
7.18 (m, 5 H, H-Bn), 7.00–6.84 (m, 2 H, NH2), 5.57 (d, 3J = 7.4 Hz, 1 H,
H-5), 5.01–4.94 (m, 1 H, H-1′), 4.62 (d, 3J = 6.1 Hz, 1 H, OH-3′), 4.53 (d,
3J = 2.7 Hz, 1 H, OH-4′), 4.25–3.97 (m, 2 H, CH2Ph), 4.03–3.97 (m, 2 H,
H-4′, H-3′), 3.33–3.29 (m, 1 H, H-6a′), 3.24 (dd, 2J = 9.7 Hz, 3J = 3.8 Hz,
1 H, H-6b′), 2.35–2.28 (m, 1 H, H-2′), 2.12–2.05 (m, 1 H, H-5a′), 1.88–
1.82 (m, 1 H, H-5b′).
13C NMR (151 MHz, DMSO-d6): δ = 165.4 (C-2), 156.3 (C-4), 144.9 (C-
6), 138.2 (Cq-Bn), 128.1 (2 × C-Bn), 127.4 (2 × C-Bn), 127.2 (C-Bn), 92.3
(C-5), 74.1 (C-3′), 72.2 (CH2Ph), 70.7 (C-4′), 68.1 (C-6′), 55.9 (C-1′), 45.3
(C-2′), 35.2 (C-5′).
The reaction was carried out according to the general isopropylidene
deprotection procedure with 12a (126 mg, 326 μmol) and acetic ac-
id/water (10 mL). Purification on silica gel (CH2Cl2/MeOH, 9:1) and
freeze-drying (MeCN/H2O, 1:1) afforded 20 (91.3 mg, 77%) as color-
less cotton-like solid.
Rf = 0.29 (CH2Cl2/MeOH, 9:1); [α]D28 –21.6 (c 0.25, MeOH).
IR (neat): 3216, 2969, 2947, 2857, 1712, 1685, 1670, 1369, 1262,
1208, 1031, 810, 755, 702, 398 cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 11.12 (br s, 1 H, NH), 7.36–7.34 (m,
1 H, H-6), 7.31–7.17 (m, 5 H, H-Bn), 5.05–4.97 (m, 1 H, H-1′), 4.97–
4.74 (m, 2 H, 2 × -OH), 4.28 (d, 2J = 12.0 Hz, 1 H, CHHPh), 4.21 (d,
2J = 12.0 Hz, 1 H, CHHPh), 4.03–3.99 (m, 1 H, H-4′), 3.97–3.93 (m, 1 H,
H-3′), 3.36–3.32 (m, 2 H, H-6′), 2.36–2.30 (m, 1 H, H-2′), 2.10 (ddd,
2J = 13.6 Hz, 3J = 9.6 Hz, 3J = 4.5 Hz, 1 H, H-5a′), 1.89 (ddd, 2J = 13.6 Hz,
3J = 8.6 Hz, 3J = 1.5 Hz, 1 H, H-5b′), 1.64 (d, 4J = 0.8 Hz, 3 H, CH3).
13C NMR (151 MHz, DMSO-d6): δ = 165.3 (Cq-4), 152.5 (Cq-2), 139.8
(C-6), 138.2 (Cq-Bn), 128.1 (2 × C-Bn), 127.3 (2 × C-Bn), 127.2 (C-Bn),
107.4 (Cq-5), 74.2 (C-3′), 72.3 (CH2Ph), 70.7 (C-4′), 68.1 (C-6′), 54.5 (C-
1′), 45.0 (C-2′), 35.1 (C-5′), 12.2 (CH3).
HRMS (ESI+): m/z [M + H]+ calcd for C17H22N3O4: 332.1605; found:
332.1606.
1′,2′-cis-(6′-O-Benzyl)-carba-ribo-adenosine [(1S,2R,3R,4S)-4-(6-
Amino-9H-purin-9-yl)-3-((benzyloxy)methyl)cyclopentane-1,2-
diol] (23)
The reaction was carried out according to the general coupling proce-
dure with 18 (136 mg, 344 μmol) and acetic acid/water (10 mL). Puri-
fication on silica gel (CH2Cl2/MeOH, 9:1) and freeze-drying
(MeCN/H2O, 1:1) afforded 23 (115 mg, 94%) as a colorless cotton-like
solid.
HRMS (ESI+): m/z [M + H]+ calcd for C18H23N2O5: 347.1601; found:
347.1604.
Rf = 0.21 (CH2Cl2/MeOH, 9:1); [α]D28 +18.8 (c 0.25, MeOH).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

I
S. Weising et al.
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Synthesis
IR (neat): 3254, 3186, 2914, 2853, 1639, 1606, 1113, 1082, 1072, 748,
702, 586 cm–1
IR (neat): 3413, 3368, 3270, 3173, 1678, 1472, 1274, 1095, 1028, 762,
.
408 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 8.11 (s, 1 H, H-8), 8.08 (s, 1 H, H-2),
7.24–7.10 (m, 5 H, 3 × H-Bn, NH2), 6.95–6.87 (m, 2 H, 2 × H-Bn), 5.29–
5.20 (m, 1 H, H-1′), 4.78 (d, 3J = 6.6 Hz, 1 H, OH), 4.66 (d, 3J = 3.1 Hz, 1
H, OH), 4.18–4.08 (m, 2 H, H-4′, H-3′), 4.01 (d, 2J = 11.8 Hz, 1 H, CH-
HPh), 3.85 (d, 2J = 11.8 Hz, 1 H, CHHPh), 3.33–3.27 (m, 1 H, H-6a′),
3.02–2.94 (m, 1 H, H-6b′), 2.57–2.50 (m, 2 H, H-2′, H-5′), 2.19–2.11
(m, 1 H, H-5b′).
13C NMR (101 MHz, DMSO-d6): δ = 156.0 (Cq-6), 152.0 (C-2), 149.9
(Cq-4), 141.4 (C-8), 137.9 (Cq-Bn), 127.9 (2 × C-Bn), 127.2 (2 × C-Bn),
127.1 (C-Bn), 119.0 (Cq-5), 74.2 (C-4′), 72.1 (CH2Ph), 70.9 (C-3′), 68.2
(C-6′), 52.8 (C-1′), 45.9 (C-2′), 36.4 (C-5′).
1H NMR (400 MHz, D2O): δ = 7.50 (q, 4J = 1.2 Hz, 1 H, H-6), 5.24–5.14
(m, 1 H, H-1′), 4.37–4.33 (m, 1 H, H-4′), 4.14 (dd, 2J = 9.3 Hz,
3J = 4.3 Hz, 1 H, H-3′), 3.69 (dd, 2J = 11.7 Hz, 3J = 4.8 Hz, 1 H, H-6a),
2
3
3.53 (dd, J = 11.7 Hz, J = 8.4 Hz, 1 H, H-6b), 2.56–2.46 (m, 1 H, H-2),
2.37–2.20 (m, 2 H, H-5a, H-5b), 1.92 (d, 4J = 1.2 Hz, 3 H, CH3).
13C NMR (101 MHz, D2O): δ = 166.6 (Cq-4), 152.7 (C-6), 141.4 (Cq-2),
110.1 (Cq-5), 74.6 (C-3′), 71.3 (C-4′), 59.3 (C-6′), 55.7 (C-1′), 46.2 (C-2′),
34.4 (C-5′), 11.4 (CH3).
HRMS (ESI+): m/z [M + H]+ calcd for C11H17N2O5: 257.1137; found:
257.1138.
Crystals for X-ray crystallographic analysis were grown from MeOH.23
HRMS (ESI+): m/z [M + H]+ calcd for C18H22N5O3: 356.1717; found:
356.1717.
1′,2′-cis-carba-ribo-Uridine [1-((1S,2R,3R,4S)-3,4-Dihydroxy-2-(hy-
droxymethyl)cyclopentyl)pyrimidine-2,4(1H,3H)-dione] (26)
1′,2′-cis-(6′-O-Benzyl)-carba-ribo-guanosine [2-Amino-9-
((1S,2R,3R,4S)-2-((Benzyloxy)methyl)-3,4-dihydroxycyclopentyl)-
1,9-dihydro-6H-purin-6-one] (24)
The diol 21 (16.6 mg, 49.9 μmol) was dissolved in dichloromethane
(2 mL) and iodotrimethylsilane (36.0 μL, 250 μmol) was added. After
stirring for 48 h at room temperature, water was added and all vola-
tiles were removed in vacuo. Purification on silica gel (CH2Cl2/MeOH,
85:15) and freeze-drying (MeCN/H2O, 1:1) afforded 26 (11.0 mg, 91%)
as a colorless cotton-like solid.
The reaction was carried out according to the general coupling proce-
dure with 19 (172 mg, 390 μmol) and acetic acid/water (12 mL). Puri-
fication on RP-18 silica gel with automated flash chromatography
(MeCN/H2O, 1:99 to 100:0) and freeze-drying (MeCN/H2O, 1:1) af-
forded 24 (130 mg, 90%) as a colorless cotton-like solid.
Rf = 0.27 (CH2Cl2/MeOH, 8:2); [α]D28 –57.2 (c 0.25, MeOH).
IR (neat): 3441, 3337, 3101, 1691, 1660, 1616, 1472, 1397, 1270,
Rf = 0.67 (CH2Cl2/MeOH, 80:20); [α]D23 +38 (c 0.1, MeOH).
1079, 1047, 768, 551, 531, 417 cm–1
.
IR (neat): 3309, 3195, 2904, 2744, 1669, 1613, 1396, 1094, 1035, 781
1H NMR (600 MHz, D2O): δ = 7.67 (d, 3J = 7.9 Hz, 1 H, H-6), 5.82 (d,
3J = 7.9 Hz, 1 H, H-5), 5.19–5.14 (m, 1 H, H-1′), 4.34–4.30 (m, 1 H, H-
4′), 4.10 (dd, 2J = 9.2 Hz, 3J = 4.3 Hz, 1 H, H-3′), 3.68 (dd, 2J = 11.8 Hz,
3J = 4.5 Hz, 1 H, H-6a), 3.51 (dd, 2J = 11.8 Hz, 3J = 8.4 Hz, 1 H, H-6b),
2.52–2.45 (m, 1 H, H-2), 2.32–2.19 (m, 2 H, H-5a, H-5b).
13C NMR (151 MHz, D2O): δ = 166.4 (Cq-4), 152.7 (C-6), 145.8 (Cq-2),
100.9 (Cq -5), 74.5 (C-3′), 71.3 (C-4′), 59.2 (C-6′), 56.0 (C-1′), 46.2 (C-
2′), 34.4 (C-5′).
cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 10.5 (br s, 1 H, NH), 7.72 (s, 1 H, H-
8), 7.26–7.19 (m, 3 H, H-Bn), 7.03–7.00 (m, 2 H, H-Bn), 6.35 (br s, 2 H,
3
NH2), 5.12–5.04 (m, 1 H, H-1′), 4.73 (d, J = 6.7 Hz, 1 H, -OH), 4.64 (d,
3J = 3.2 Hz, 1 H, -OH), 4.10–4.00 (m, 3 H, CHH-Ph, H-4′, H-3′), 3.93 (d,
2J = 11.7 Hz, 1 H, CHH-Ph), 3.35–3.30 (m, 1 H, H-6a′), 3.13–3.07 (m, 1
H, H-6b′), 2.45–2.38 (m, 1 H, H-2′), 2.34–2.28 (m, 1 H, H-5a′), 2.13–
2.07 (m, 1 H, H-5b′).
HRMS (ESI+): m/z [M + H]+ calcd for C10H15N2O5: 243.0981; found:
243.0977.
13C NMR (151 MHz, DMSO-d6): δ = 156.9 (C-6), 153.1 (C-2), 151.6 (C-
4), 138.1 (Cq-Bn), 137.3 (C-8), 128.0 (2 × C-Bn), 127.2 (2 × C-Bn), 127.1
(C-Bn), 116.5 (C-5), 74.2 (C-3′), 72.1 (CH2Ph), 70.7 (C-4′), 68.3 (C-6′),
51.7 (C-1′), 45.8 (C-2′), 36.8 (C-5′).
1′,2′-cis-carba-ribo-Cytidine [4-Amino-1-((1S,2R,3R,4S)-3,4-dihy-
droxy-2-(hydroxymethyl)cyclopentyl)pyrimidin-2(1H)-one] (27)
HRMS (ESI+): m/z [M + H]+ calcd for C18H22N5O4: 372.1666; found:
The cytidine derivative 22 (38.1 mg, 115 μmol) was dissolved in
methanol (7 mL) and cyclohexene (3 mL). Pd(OH)2/C (20%, 23 mg) was
added and the reaction mixture was heated to reflux overnight. Puri-
fication on silica gel (CH2Cl2/MeOH, 85:15) and freeze-drying
(MeCN/H2O, 1:1) afforded 27 (25.1 mg, 91%) as a colorless cotton-like
solid.
372.1671.
Debenzylation; General Procedure
To a solution of the appropriate benzyl ether in methanol was added
Pd/C (10%) and the mixture was stirred under a H2 atmosphere at
room temperature. After full conversion, the mixture was filtered
through Celite® and washed with dichloromethane/methanol (2:1).
After evaporation of the solvent, the residue was purified as indicat-
ed.
Rf = 0.13 (CH2Cl2/MeOH, 80:20); [α]D23 –95 (c 0.1, MeOH).
IR (neat): 3327, 3198, 2928, 1634, 1602, 1485, 1405, 1284, 1082,
1037, 786 cm–1
.
1H NMR (400 MHz, D2O): δ = 7.59 (d, 3J = 7.5 Hz, 1 H, H-6), 5.97 (d,
3J = 7.5 Hz, 1 H, H-5), 5.18–5.07 (m, 1 H, H-1′), 4.35–4.30 (m, 1 H, H-
4′), 4.14 (dd, 3J = 8.8 Hz, 3J = 4.4 Hz, 1 H, H-3′), 3.56 (dd, 2J = 11.7 Hz,
3J = 4.9 Hz, 1 H, H-6a′), 3.47 (dd, 2J = 11.7 Hz, 3J = 7.5 Hz, 1 H, H-6b′),
2.52–2.42 (m, 1 H, H-2′), 2.28 (ddd, 2J = 14.4 Hz, 3J = 9.1 Hz, 3J = 4.9 Hz,
1 H, H-5a′), 2.18 (ddd, 2J = 14.4 Hz, 3J = 8.6 Hz, 3J = 1.8 Hz, 1 H, H-5b′).
13C NMR (101 MHz, D2O): δ = 165.9 (Cq-4), 158.8 (Cq-2), 145.3 (C-6),
95.1 (C-5), 74.6 (C-3′), 71.2 (C-4′), 59.3 (C-6′), 56.8 (C-1′), 46.5 (C-2′),
34.6 (C-5′).
1′,2′-cis-carba-ribo-Thymidine [1-((1S,2R,3R,4S)-3,4-Dihydroxy-2-
(hydroxymethyl)cyclopentyl)-5-methylpyrimidine-2,4(1H,3H)-di-
one] (25)
The reaction was carried out according to the general procedure with
20 (82.1 mg, 23.7 μmol) and methanol (10 mL). Purification on silica
gel (CH2Cl2/MeOH, 85:15) and freeze-drying (MeCN/H2O, 1:1) afford-
ed 25 (56.8 mg, 94%) as a colorless cotton-like solid.
Rf = 0.20 (CH2Cl2/MeOH, 85:15); [α]D28 –1.2 (c 0.25, MeOH).
HRMS (ESI+): m/z [M + H]+ calcd for C10H16N3O4: 242.1135; found:
242.1141.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

J
S. Weising et al.
Paper
Synthesis
1′,2′-cis-carba-ribo-Adenosine [(1S,2R,3R,4S)-4-(6-Amino-9H-pu-
rin-9-yl)-3-(hydroxymethyl)cyclopentane-1,2-diol] (28)
References
(1) Marquez, V.-E.; Lim, M.-I. Med. Chem. Rev. 1986, 6, 1.
(2) Marquez, V.-E. In Advances in Antiviral Drug Design;V2
The reaction was carried out according to the general procedure with
23 (63.4 mg, 178 μmol) and methanol (10 mL). Purification on silica
gel (CH2Cl2/MeOH, 85:15) and freeze-drying (MeCN/H2O, 1:1) afford-
ed 28 (34.3 mg, 73%) as a colorless cotton-like solid.
ol
De Clercq,
E., Ed.; JAI Press Inc: London, 1996, 89–146.
(3) (a) Borthwick, A. D.; Biggadike, K. Tetrahedron 1992, 48, 571.
(b) Agrofoglio, L.; Suhas, E.; Farese, A.; Condom, R.; Challand, S.
R.; Earl, R. A.; Guedj, R. Tetrahedron 1994, 50, 10611. (c) Wang,
J.; Jin, Y.; Rapp, K. L.; Schinazi, R. F.; Chu, C. K. J. Med. Chem.
2007, 50, 1828. (d) Nishiyama, S.; Ueki, S.; Watanabe, T.;
Yamamura, S.; Kato, K.; Takita, T. Tetrahedron Lett. 1991, 32,
2141. (e) Zhao, Y.; Yang, T.; Lee, M.; Lee, D.; Newton, M. G.; Chu,
C. K. J. Org. Chem. 1995, 60, 5236. (f) Racine, S.; de Nanteuil, F.;
Serrano, E.; Waser, J. Angew. Chem. Int. Ed. 2014, 53, 8484.
(g) Xie, M.-S.; Zhou, P.; Niu, H.-Y.; Qu, G.-R.; Guo, H.-M. Org. Lett.
2016, 18, 4344. (h) Huang, K.-X.; Xie, M.-S.; Zhao, G.-F.; Qu, G.-
R.; Guo, H.-M. Adv. Synth. Catal. 2016, 358, 3627.
Rf = 0.27 (CH2Cl2/MeOH, 4:1); [α]D28 +7.2 (c 0.25, MeOH).
IR (neat): 3313, 3181, 2920, 2854, 1636, 1597, 1571, 1475, 1414,
1330, 1302, 1247, 1095, 1036, 642, 572 cm–1
.
1H NMR (400 MHz, D2O): δ = 8.23 (s, 1 H, H-2), 8.20 (s, 1 H, H-8),
5.43–5.34 (m, 1 H, H-1′), 4.49–4.44 (m, 1 H, H-4′), 4.28 (dd, 3J = 9.3 Hz,
3J = 4.4 Hz, 1 H, H-3′), 3.49 (dd, 2J = 11.7 Hz, 3J = 4.7 Hz, 1 H, H-6a′),
2
3
3.26 (dd, J = 11.7 Hz, J = 7.8 Hz, 1 H, H-6b′), 2.68–2.58 (m, 2 H, H-2,
H-5a′), 2.49 (ddd, 2J = 15.0 Hz, 3J = 8.7 Hz, 3J = 1.9 Hz, 1 H, H-5b′).
13C NMR (101 MHz, D2O): δ = 155.1 (Cq-6), 151.9 (C-2), 149.2 (Cq-4),
141.6 (C-8), 118.1 (C-5), 74.3 (C-3′), 71.1 (C-4′), 59.0 (C-6′), 52.8 (C-1′),
46.9 (C-2′), 35.8 (C-5′).
HRMS (ESI+): m/z [M + H]+ calcd for C11H16N5O3: 266.1248; found:
266.1246.
(4) (a) Seley, K. L.; Schneller, S. W.; Korba, B. Nucleosides Nucleotides
1997, 12, 2095. (b) Zimmermann, S. C.; Sadler, J. M.; Andrei, G.;
Snoeck, R.; Balzarini, J.; Seley-Radtke, K. L. Med. Chem. Commun.
2011, 2, 650.
(5) (a) Daluge, S. M.; Good, S. S.; Faletto, M. B.; Miller, W. H.; St.
Clair, M. H.; Boone, L. R.; Tisdale, M.; Parry, N. R.; Reardon, J. E.;
Dornsife, R. E.; Averett, D. R.; Krenitsky, T. Antimicrob. Agents
Chemother. 1997, 41, 1082. (b) Daluge, S. M.; Martin, M. T.;
Sickles, B. R.; Livingston, D. A. Nucleosides Nucleotides Nucleic
Acids 2000, 19, 297. (c) Faletto, M. B.; Miller, W. H.; Garvey, E. P.;
St. Clair, M. H.; Daluge, S. M.; Good, S. S. Antimicrob. Agents
Chemother. 1997, 41, 1099.
1′,2′-cis-carba-ribo-Guanosine [2-Amino-9-((1S,2R,3R,4S)-3,4-di-
hydroxy-2-(hydroxymethyl)cyclopentyl)-1,9-dihydro-6H-purin-6-
one] (29)
The reaction was carried out according to the general procedure with
24 (31.6 mg, 85.0 μmol) and methanol (5 mL). Purification on RP-18
silica gel (H2O/MeCN, 98:2 to 0:100) and freeze-drying (MeCN/H2O,
1:1) afforded 29 (13.5 mg, 56%) as a colorless cotton-like solid.
(6) (a) Bisacchi, G. S.; Chao, S. T.; Bachard, C.; Daris, J. P.; Innaimo,
S.; Jacobs, G. A.; Kocy, O.; Lapointe, P.; Martel, A.; Mechant, Z.;
Slusachyk, W. A.; Sundeen, J. E.; Young, M. G.; Colonno, R.;
Zahler, R. Med. Chem. Lett. 1997, 7, 127. (b) Levine, S.;
Hernandez, D.; Yamanaka, G.; Zhang, S.; Rose, R.; Weinheimer,
S.; Colonno, R. J. Antimicrob. Agents Chemother. 2002, 46, 2525.
(7) Mahler, M.; Reichardt, B.; Hartjen, P.; van Lunzen, J.; Meier, C.
Chem. Eur. J. 2012, 18, 11046.
Rf = 0.13 (CH2Cl2/MeOH, 80:20); [α]D23 +3.0 (c 0.1, MeOH/H2O).
IR (neat): 3323, 3197, 2922, 2870, 1568, 1473, 1397, 1339, 1070,
1026, 801, 699 cm–1
.
1H NMR (500 MHz, D2O): δ = 7.78 (s, 1 H, H-8), 5.16–5.06 (m, 1 H, H-
1′), 4.44–4.37 (m, 1 H, H-4′), 4.24–4.17 (m, 1 H, H-3′), 3.56–3.49 (m, 1
H, H-6a′), 3.28–3.20 (m, 1 H, H-6b′), 2.59–2.46 (m, 2 H, H-2′, H-5a′),
2.45–2.36 (m, 1 H, H-5b′).
(8) Gollnest, T.; de Oliveira, T. D.; Rath, A.; Hauber, I.; Schols, D.;
Balzarini, J.; Meier, C. Angew. Chem. 2016, 128, 5341.
(9) Ludek, O. R.; Krämer, T.; Balzarini, J.; Meier, C. Synthesis 2006,
1313.
(10) Santana, L.; Teijeira, M.; Uriarte, E.; Balzarini, J.; De Clerq, E.
Nucleosides Nucleotides 1995, 14, 521.
13C NMR (126 MHz, D2O): δ = 159.3 (C-6), 153.9 (C-2), 152.4 (C-4),
139.7 (C-8), 116.2 (C-5), 74.6 (C-3′), 71.5 (C-4′), 59.6 (C-6′), 52.9 (C-1′),
47.6 (C-2′), 36.5 (C-5′).
HRMS (ESI+): m/z [M + H]+ calcd for C11H16N5O4: 282.1197; found:
282.1201.
(11) Biggadike, K.; Borthwick, A. D.; Evans, D.; Exall, A. M.; Kirk, B. E.;
Roberts, S. M.; Stephenson, L.; Youds, P. J. Chem. Soc., Perkin
Trans. 1 1988, 549.
(12) Jessel, S.; Meier, C. Eur. J. Org. Chem. 2011, 1702.
(13) Cossy, J.; Ranaivosata, J.-L.; Bellosta, V.; Wietzke, R. Synth.
Commun. 1995, 25, 3109.
Funding Information
The authors are grateful to Universität Hamburg and the Italian MIUR
fund – (PRIN 2009, Prot. N. 20094Bj9R7_002) for financial support.
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(14) (a) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
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Acknowledgment
We are grateful to Frank Hoffmann for his excellent support with the
crystal structure analysis.
(15) (a) Ludek, O. R.; Meier, C. Synlett 2005, 3145. (b) Ludek, O. R.;
Meier, C. Synlett 2006, 324. (c) Ludek, O. R.; Meier, C. Eur. J. Org.
Chem. 2006, 941.
Supporting Information
(16) Radi, M.; Rao, J. R.; Jha, A. K.; Chu, C. K. Nucleosides Nucleotides
Nucleic Acids 2009, 28, 504.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1591732.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

K
S. Weising et al.
Paper
Synthesis
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data for this paper. The data can be obtained free of charge from
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The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K