Synthesis of Enantiomerically Pure 1′,2′- cis - Dideoxy, - dideoxydidehydro, - Ribo and - Deoxy Carbocyclic Nucleoside Analogues

Article abstract of DOI:10.1055/s-0037-1609493

We describe a short and stereospecific synthesis of different series of 1′,2′- cis -disubstituted carbocyclic nucleoside analogues. All-natural nucleobases or their precursors are coupled in a microwave-assisted Mitsunobu-type reaction with enantiomerically pure (1 R,2 S)-2-(benzyloxymethyl)cyclopent-3-enol. By modifying the cyclopentene scaffold, our synthetic strategy gives access to a series of 1′,2′- cis -disubstituted carbocyclic nucleoside analogues of the dideoxy (dd), dideoxydidehydro (d 4) or the ribo series. The ribo series is synthesized in a more convenient way compared to a previous route. The deoxy series of 1′,2′- cis -disubstituted carbocyclic nucleoside analogues is prepared following an earlier reported approach. This synthesis involves the microwave-assisted coupling of (1 R,2 S,3 S)-3-(benzyloxy)-2-[(benzyloxy)methyl]cyclopentan-1-ol with the appropriate nucleobases.

Full text of DOI:10.1055/s-0037-1609493

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–O
paper
A
en
S. Weising et al.
Paper
Synthesis
Synthesis of Enantiomerically Pure 1′,2′-cis-dideoxy, -dideoxydi-
dehydro, -ribo and -deoxy Carbocyclic Nucleoside Analogues
OH
Simon Weisinga
BnO
Patrick Dekierta
Dominique Scholsb
Johan Neytsb
BnO
HO
2–3 steps
2–3 steps
3–4 steps
4–5 steps
Chris Meier*a
a Organische Chemie, Fakultät für Mathematik, Informatik
und Naturwissenschaften, Universität Hamburg, Martin-
Luther-King-Platz 6, 20146 Hamburg, Germany
chris.meier@chemie.uni-hamburg.de
b Katholieke Universiteit Leuven, Rega Institute for Medical
Research, Herestraat 49, 3000 Leuven, Belgium
nucleobase
OH
nucleobase
nucleobase
nucleobase
HO
HO
HO
HO
HO
HO
5–16%
27–52%
23–47%
28–41%
nucleobase = T, U, C, A, G
Received: 25.01.2018
Accepted after revision: 06.03.2018
Published online: 12.04.2018
pentyl core leads to improved hydrolytic stability, higher
bioavailability and a conformational change of the carbo-
cyclic skeleton which influences the biological activity.4 The
carbocyclic nucleoside analogues abacavir5 and entecavir6
were found to be active against HIV and HBV, respectively,
and were approved for clinical use, e.g., in the United States
in 1998 and 2005, respectively. Moreover, in 1995 and
2006, respectively, carbocyclic nucleoside analogues [(±)-1
and (–)-2] with a 1′,2′-cis-substitution pattern (with regard
to the arrangement of the nucleobase and the hydroxy-
methyl substituent; see Figure 1) were first described to
exhibit moderate anti-HIV activity.7 In addition, in 1998,
both enantiomers of compound 3 were found to be selec-
tive competitive inhibitors of the terminal deoxynucleoti-
dyl transferase (TdT).8 This generally shows that the 1′,2′-
cis-substitution pattern in carbocyclic nucleoside analogues
provides a promising approach for the design of innovative
inhibitors. To test this hypothesis, we describe here a short
and convenient synthetic strategy that reliably provides
stereochemically pure 1′,2′-cis-substituted carbocyclic
nucleoside analogues that are based on three (dideoxy (dd),
dideoxydidehydro (d4), ribo) different carbocyclic scaffolds.
Our synthesis started with a microwave-assisted Mitsu-
nobu-type reaction of the appropriate nucleobase, or its
precursor, and enantiomerically pure (1R,2S)-2-(benzy-
loxymethyl)cyclopent-3-enol [(1R,2S)-4]. The cyclopentene
scaffold allowed diverse modifications at the 3′- and 4′-po-
sitions of these 1′,2′-cis-substituted carbocyclic nucleo-
sides. In this way, the syntheses of d4-, dd- and ribo-ana-
logues were achieved. (1R,2S)-2-(Benzyloxymethyl)cyclo-
pent-3-enol (4) was first introduced by Biggadike et al. in
the synthesis of carbocyclic nucleosides, and later became
central to many routes leading to these compounds.6a,9 In
the literature there are many examples of microwave-
assisted reactions including Mitsunobu reactions which led
DOI: 10.1055/s-0037-1609493; Art ID: ss-2018-z0050-op
Abstract We describe a short and stereospecific synthesis of different
series of 1′,2′-cis-disubstituted carbocyclic nucleoside analogues. All-
natural nucleobases or their precursors are coupled in a microwave-as-
sisted Mitsunobu-type reaction with enantiomerically pure (1R,2S)-2-
(benzyloxymethyl)cyclopent-3-enol. By modifying the cyclopentene
scaffold, our synthetic strategy gives access to a series of 1′,2′-cis-
disubstituted carbocyclic nucleoside analogues of the dideoxy (dd), di-
deoxydidehydro (d4) or the ribo series. The ribo series is synthesized in a
more convenient way compared to a previous route. The deoxy series of
1′,2′-cis-disubstituted carbocyclic nucleoside analogues is prepared fol-
lowing an earlier reported approach. This synthesis involves the micro-
wave-assisted coupling of (1R,2S,3S)-3-(benzyloxy)-2-[(benzyl-
oxy)methyl]cyclopentan-1-ol with the appropriate nucleobases.
Key words carbocycles, Mitsunobu coupling, 1′,2′-cis-substitution,
microwave reaction, nucleosides
Viral infections continue to massively impact modern
society and for many virus-caused infections, still no effec-
tive therapeutics or vaccines are available. Nucleoside ana-
logues are one class of antiviral agents which mostly target
the replication of the virus genome by blocking viral poly-
merases.1 Over the last decades, various nucleoside ana-
logues or their nucleotide prodrugs have been approved for
treatment of infectious diseases caused by viral pathogens,
such as lamivudin (3TC)2 against HIV and sofosbuvir3
against HCV. The modifications in such nucleoside ana-
logues are not limited to the nucleobases, as the glycon can
be chemically modified as well. One of these modifications
is the replacement of the ring oxygen atom by a methylene
group. Due to their beneficial biological properties, the de-
velopment of carbocyclic nucleosides became an integral
element in the development of innovative nucleoside ana-
logues to combat viral infections. The five-membered cyclo-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

B
S. Weising et al.
Paper
Synthesis
Table 1 Mitsunobu Coupling of Cyclopentenol 4 with Pyrimidines
Using Microwave-Assistance (A) or Conventional Conditions (B)
O
N
O
N
I
NH
NH
R'
O
O
R
R
N
N
HO
HO
OH
O
N
R'
N
O
Method A or B
solvent
HO
N
(
)-1
(–)-2
5b–7b
BnO
BnO
NH2
O2-alkylation
O
O
P
4
O
5a–7a
R = Me, R' = OH 5
R = H, R' = OH
R = H, R' = NH2
P
O
N
N
6
7
O
P
N1-alkylation
O
O
O
O
N
O
Entry
1
Nucleobase Methoda (time)
Solvent
MeCN
Product (yield, %)
cis-(+)-3 and cis-(–)-3
TBz
TBz
UBz
UBz
CAc
CAc
A (1 h)
5a (37)b
5b (8)
Figure 1 Known active 1′,2′-cis-disubstituted carbocyclic nucleosides
2
3
4
5
6
B (24 h)
A (2 h)
MeCN
MeCN
MeCN
MeCN
THF
5a (38)b
5b (n.d.)
to a decreased reaction time and a higher yield.10 Recently,
we reported on a microwave-assisted Mitsunobu-type reac-
tion for the synthesis of 1′,2′-cis-disubstituted ribo-carbo-
cyclic nucleosides.11 Employing this technique, the reaction
time was decreased from several days using conventional
conditions to about 2 hours. The yields were comparable,
but importantly, the purification was simplified since the
amounts of reagents could be drastically reduced.
6a (46)b
6b (5)
B (48 h)
A (0.5 h)
A (0.5 h)
6a (44)b
6b (n.d.)
7a (n.a.)c
7b (25)
7a (n.a.)c
7b (45)
a Method A: PPh3 (1.5 equiv), DIAD (1.5 equiv), nucleobase (1.5 equiv), sol-
vent, microwave reaction ‘open vessel’, 100 W, 50 °C, (30 min intervals until
full conversion); Method B: PPh3 (3.0 equiv), DIAD (2.8 equiv), nucleobase
(2.2 equiv), solvent, –40 °C to r.t.
The reaction of enantiomerically pure cyclopentenol 4
with the N3-protected pyrimidines was performed in
MeCN to minimize the formation of the O2-alkylated side
product.11,12 Accordingly, the thymine and uracil analogues
5a and 6a were obtained in 37% and 46% yield, respectively
(Table 1). The standard Mitsunobu reaction led to nearly the
same yields (38% and 44%, respectively), but as mentioned
before, the reaction time was considerably longer and the
excess of Mitsunobu reagents had to be removed after the
reaction.11
The 6-chloropurines were coupled using the same pro-
cedure; however, in these cases, the use of THF instead of
MeCN as the solvent resulted in improved yields. 6-Chloro-
purine- (8) and 2-amino-6-chloropurine derivatives (9)
were obtained in 60% and 59% yield, respectively (Table 2).
The use of 2-isobutylamino-6-chloropurine13 and a direct
substitution with formic acid and amide cleavage led to the
guanine derivative 10 in 52% yield. As is known from earlier
work, the direct coupling of N4-acetylcytosine to cyclo-
pentenol 7a was not successful due to the exclusive form-
b Including deprotection with NaOH in MeOH. n.d. = not determined.
c Only O2-alkylation was observed; n.a. = not available
ation of the undesired O2-alkylated product 7b.11 Thus, cy-
tosine derivative 7a was prepared by the classic conversion
of the uracil derivative 6a with 1H-1,2,4-triazole, POCl3 and
Et3N with subsequent substitution with aqueous NH3
(Scheme 1).14
Treatment of the 6-chloropurine derivative 8 with 7 M
NH3 in MeOH afforded adenosine derivative 11 in 51% yield.
However, when the methanolic solution was replaced with
25% aqueous NH3 in MeCN, the yield was increased to 97%
(Scheme 2). 2-Amino-6-chloropurine derivative 9 was heat-
ed under reflux in 0.5 M aqueous sodium hydroxide solu-
tion and thus provided the corresponding guanosine deriv-
ative 10.15
For the preparation of the dideoxydidehydro analogues,
the benzyl group was cleaved first. The olefinic bond in the
cyclopentene scaffold precluded a hydrogenolytic cleavage
with a palladium catalyst. Another approach to cleave
benzyl ethers makes use of Lewis acids. Therefore, benzyl
ether cleavage from compounds 5a, 6a, 7a, 11 and 10 with
different Lewis acids (ZnCl2, BCl3 and TMSI)16 was applied
(Table 3) and the dideoxydidehydro analogues were ob-
tained in yields of 71% to quantitative. In most cases, the
O
N
NH2
1) 1,2,4-triazole, POCl3
Et3N, MeCN
2) aq NH4OH
NH
N
O
N
O
74%
BnO
BnO
6a
7a
Scheme 1 Conversion of uracil derivative 6a into the cytosine
compound 7a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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Synthesis
Table 2 Mitsunobu Coupling of Cyclopentenol 4 with 6-Chloropurines
Table 3 De-O-benzylation with Lewis Acids
Using Microwave Assistance (A) or Conventional Conditions (B)
nucleobase
Method A–C
nucleobase
R
N
N
BnO
HO
N
OH
N
R'
5a, 6a, 7a, 11, 10
12–16
Method A or B
solvent
BnO
BnO
Entry
Nucleobase (substrate) Methoda
Product (yield%)
R = Cl, R' = H
R = Cl, R' = NH2
8
9
4
8–10
1
2
3
4
5
6
7
8
9
T (5a)
T (5a)
U (6a)
U (6a)
C (7a)
A (11)
A (11)
G (10)
G (10)
A
B
A
B
B
A
B
B
C
12 (74)
12 (72)
13 (50)
13 (91)
14 (100)
15 (71)
15 (88)
16 (100)
16 (82)
R = OH, R' = NH2 10
Entry Nucleobase
Methoda
(time)
Solvent Product
(yield%)
1
2
3
4
5
6
7
8
6-chloropurine
A (0.5 h)
A (1 h)
MeCN
THF
8 (45)
8 (60)
9 (40)
9 (59)
9 (33)
9 (41)
10 (20)b
10 (52)b
6-chloropurine
2-amino-6-chloropurine
2-amino-6-chloropurine
2-amino-6-chloropurine
2-amino-6-chloropurine
A (0.5 h)
A (1 h)
MeCN
THF
B (72 h)
B (48 h)
MeCN
THF
a Method A: (i) ZnCl2, Ac2O/AcOH (5:1), r.t.; (ii) 1% NaOH in MeOH, r.t.;
Method B: BCl3, CH2Cl2, –78 °C to –20 °C; Method C: TMSI, CH2Cl2, r.t.
2-isobutylamino-6-chloropurine A (2.5 h)
2-isobutylamino-6-chloropurine A (0.5 h)
MeCN
THF
a For methods A and B, see Table 1.
b Including: (i) formic acid, reflux; (ii) 7 M NH3 in MeOH, r.t.
cytidine derivative 19 was finally obtained by the conver-
sion of the acetylated uridine derivative generated from 18
with 1H-1,2,4-triazole, POCl3 and triethylamine (analogous
to Scheme 1) in a 64% overall yield.
Recently, we reported a stereoselective seven-step route
to 1′,2′-cis-disubstituted ribo-configured carbocyclic nucle-
osides.11 With the new route reported here, these ribo com-
pounds can be prepared in only four steps. The cyclopen-
tene scaffold of derivatives 5a, 6a, 7a, 11 and 10 was cis-di-
hydroxylated with AD-mix α or β, respectively.19 With the
Cl
R'
N
N
N
N
N
(a) R = H
(b) R = NH2
N
N
N
R
R
BnO
BnO
R = H
8
R = NH2, R' = OH 10
R = H, R' = NH2 11
R = NH2
9
Scheme 2 Reagents and conditions: (a) 25% aq NH4OH, MeCN, micro-
wave (50 W), 70 °C; (b) 0.5 M aq NaOH, reflux.
Table 4 Simultaneous Hydrogenolytic Cleavage of the Benzyl Ether
and Hydrogenation of the Olefin
use of BCl3 in CH2Cl2 at low temperatures proved to be fa-
vorable and the deprotected analogues 12–16 were ob-
tained after simple and fast chromatographic purification.
For the synthesis of the dideoxy analogues,8,17 simulta-
neous hydrogenolytic cleavage of the benzyl ether and hy-
drogenation of the olefinic bond provided derivatives 17,
18, 20 and 21. All four compounds were obtained using
standard conditions with 10% palladium on charcoal and
molecular hydrogen (Table 4).
However, with regard to the cytidine derivative 7a, the
use of the palladium catalyst and molecular hydrogen did
not lead to the desired cytidine derivative 19 (Table 3, en-
tries 3 and 4). A possible side reaction is the hydrogenation
of the nucleobase.18 Applying milder conditions with cyclo-
hexene as the hydrogen source led to the formation of the
desired product, but the simultaneous formation of a side
product gave an inseparable mixture (ratio 3:1). Therefore,
nucleobase
nucleobase
Method A or B
BnO
HO
5a, 6a, 7a, 11, 10
17–21
Entry
Nucleobase (substrate) Methoda
Product (yield%)
1
2
3
4
5
6
T (5a)
U (6a)
C (7a)
C (7a)
A (11)
G (10)
A
A
A
B
A
A
17 (68)
18 (79)
19 (–)b
19 (–)c
20 (80)
21 (87)
a Method A: Pd/C (10%), H2, MeOH, r.t.; Method B: Pd(OH)2/C (20%),
MeOH, cyclohexene, reflux.
b No formation of 19 detected.
c Formation of an inseparable mixture of two products (3:1).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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Synthesis
use of AD-mix β in all cases, the ribo isomer was exclusively
formed, whereas AD-mix α led to the formation of traces of
the lyxo isomer for the derivatives 22, 23 and 24 (Table 5). A
determination of the exact diastereomeric ratio was not
possible due to the high amounts of reagents in the crude
mixture that interfered with standard analytical tech-
niques. The reaction was performed in a mixture of tert-
butanol/water (2:1) at room temperature since lower tem-
peratures led to longer reaction times or even incomplete
conversion.
nucleobase
OH
nucleobase
OH
ref. 11
BnO
HO
HO
HO
22–26
27–31 (56–94%)
Scheme 3 Benzyl deprotection of compounds 22–26
OH
ref. 7b
BnO
BnO
24% over
2 steps
HO
BnO
32
Table 5 Dihydroxylation Reaction Using AD-mix
(1S,2R)-4
AD-mix
MeSO2NH2
Scheme 4 Preparation of coupling precursor 32
nucleobase
nucleobase
t-BuOH/H2O
BnO
BnO
The synthesis of 32 involved a benzylation reaction fol-
lowed by a hydroboration, and the desired coupling precur-
sor 32 was obtained in 24% yield over two steps. Next, the
microwave-assisted Mitsunobu-type reaction was again ap-
plied for the coupling of the appropriate nucleobase with
32 (Table 6).
HO
22–26
OH
5a, 6a, 7a, 11, 10
Entry
Nucleobase (substrate) AD-mix
Product (yield%)
1
2
T (5a)
T (5a)
U (6a)
U (6a)
C (7a)
C (7a)
A (11)
A (11)
G (10)
G (10)
α
β
α
β
α
β
α
β
α
β
22 (86)
22 (89)
23 (83)
23 (95)
24 (83)
24 (97)
25 (96)
25 (97)
26 (95)
26 (95)
3
Table 6 Mitsunobu Coupling of 32
4
nucleobase, PPh3
5
DIAD, solvent
microwave (100 W)
50 °C
OH
nucleobase
6
7
BnO
BnO
8
BnO
BnO
33–38
9
32
10
Entry
Nucleobase
Solvent
Product
(yield%)
Generally, the use of AD-mix β led to higher yields and
the benzyl protected ribo analogues were obtained in 89–
97% yield. These compounds showed identical analytical
data as published before. The overall yields for compounds
22–26 starting from 4 (33–56%) exceeded those previously
reported (8–35%).11 While for the purines the increase in
yield could be explained by the lowering of the total num-
ber of chemical steps, the results for pyrimidines are even
more significant due to the enhanced efficiency of the Mit-
sunobu reaction.11
The debenzylation of compounds 22–26 (Scheme 3) was
accomplished with either 10% palladium on charcoal or 20%
palladium hydroxide on charcoal to afford products 27–31;
these reactions were published previously.11
The deoxy series was prepared based on an earlier re-
ported route by us for the synthesis of 1′,2′-cis-substituted
deoxy carbocyclic thymidine 2. Therefore, compound 32
was initially prepared according to the literature protocol
(Scheme 4).7b
1
2
3
4
TBz
UBz
CAc
CAc
MeCN
MeCN
MeCN
THF
33a (39)a
33b (24)
34a (31)a
34b (17)
35a (n.a.)b
35b (49)
35a (n.a.)b
35b (67)
5
6
7
6-chloropurine
THF
THF
THF
36 (78)
37 (67)
38 (31)c
2-amino-6-chloropurine
2-isobutylamino-6-chloropurine
a Including deprotection with NaOH in MeOH.
b Only formation of the O2-alkylation product was observed; n.a. = not avail-
able.
c Including: (i) formic acid, reflux; (ii) 7 M NH3 in MeOH, r.t.
Again, the pyrimidines were reacted in MeCN (Table 6,
entries 1–3), whereas THF was used for 6-chloropurines
(entries 5–7). The yields were comparable to those ob-
tained for derivatives 5a–10 described above. The thymine
(33a) and uracil derivatives (34a) were obtained in 39% (Lit.
43%)7b and 31% yields, respectively, and the 6-chloropurine
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

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S. Weising et al.
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Synthesis
derivatives (36 and 37) were isolated in yields of 78% and
67%, respectively. The reaction with 2-isobutylamino-6-
chloropurine led to the guanosine derivative 38 in 31%
yield. The Mitsunobu reaction with N4-acetylcytosine again
led only to the selective formation of the O2-alkylated prod-
uct 35b. Thus, as before (Scheme 1), the cytosine derivative
35a was prepared by the conversion of the corresponding
uracil derivative 34a in 77% yield.
The deoxy 6-chloropurine derivatives 36 and 37 were
treated analogously to those in the above-mentioned series
(Scheme 2) to afford the corresponding adenosine 39 and
guanosine derivatives 38 in 98% and 92% yield, respectively.
The results of the final benzyl ether cleavage reactions
are listed in Table 7. Derivatives 33a, 39 and 38 underwent
hydrogenolytic cleavage using palladium (10%) on charcoal
and molecular hydrogen to afford the deoxy analogues 40,
43 and 44 in yields of 83–93% (Table 7). The benzyl ether of
the cytidine derivative 35a was cleaved using palladium hy-
droxide (20%) on charcoal and cyclohexene as the hydrogen
source to provide the cytidine nucleoside 42 in 88% yield.20
Debenzylation of the uracil derivative 34a was successful
with either Lewis acids or mild hydrogenolysis (entries 2
and 3).
YF) because of their diverse ribose analogue structures, but
none of the compounds exhibited antiviral activity (>33
μg/mL).
In conclusion, we have synthesized four series of enan-
tiomerically pure 1′,2′-cis-disubstituted carbocyclic nucleo-
side analogues by developing a short synthetic route. With
our strategy, dideoxydidehydro- (d4), dideoxy- (dd) and ribo-
analogues were accessible starting from (1R,2S)-2-(benzy-
loxymethyl)cyclopent-3-enol in a highly reliable and conve-
nient manner. The deoxy analogues were synthesized fol-
lowing our earlier reported approach.
None of the presented nucleoside analogues showed an-
tiviral activity. Thus, in the future, we will include these
compounds in our three pronucleotide approaches which
proved either to deliver the corresponding nucleoside
mono-, di- or triphosphate analogue.
All experiments involving water- or air-sensitive compounds were
carried out under anhydrous conditions (N2 atmosphere). Reagents
were purchased from various suppliers and were used without fur-
ther purification, unless otherwise noted. Anhydrous solvents were
purchased from Acros Organics (extra dry over molecular sieves) or
dried using a MBraun (MB SPS-800)-System. Solvents for chromatog-
raphy were purchased in technical grade and distilled prior to use. Ul-
trapure water and MeCN for reverse-phase chromatography was puri-
fied using a Sartorius Aurium pro apparatus (Sartopore 0.2 μm, UV)
and purchased from VWR (HPLC grade), respectively. Column chro-
matography on silica gel was performed using Macherey Nagel silica
gel MN 60 M (0.04–0.063 mm). Thin-layer chromatography was per-
formed on Macherey Nagel precoated TLC sheets (ALUGRAM® Xtra SIL
G/UV254). Visualization of non-UV-active compounds was achieved by
heat-staining with vanillin in sulfuric acid, acetic acid and MeOH. Au-
tomated flash reverse-phase chromatography was performed using
MN RS 16 C18 ec, RS 40 C18 ec or RS 120 C18 ec columns on an Inter-
chim Puriflash 430 system. Microwave-assisted reactions were con-
ducted in a CEM discover system in open- or closed-vessel mode at
different temperatures and power. Optical rotations were measured
with a P8000 polarimeter (A. Krüss Optonic GmbH) at the indicated
temperatures. IR spectra were recorded on a Bruker Alpha IR spectro-
photometer. NMR solvents were purchased from Euroiso-Top (CDCl3,
CD3OD and D2O) and Deutero (DMSO-d6). NMR-spectra were record-
ed at room temperature on Bruker Fourier 300, Bruker Avance I 400,
DRX 500 and Avance III 600 instruments. High-resolution mass spec-
trometry was performed using an Agilent 6224 ESI-TOF instrument.
Table 7 Debenzylation of the deoxy Series Analogues
nucleobase
nucleobase
Method A–C
BnO
HO
BnO
HO
33a, 34a, 35a, 39, 38
40–44
Entry
Nucleobase (substrate) Methoda
Product (yield%)
1
2
3
4
5
6
7
T (33a)
U (34a)
U (34a)
C (35a)
A (39)
A
B
C
C
A
B
A
40 (93)
41 (56)
41 (77)
42 (88)
43 (83)
43 (85)
44 (92)
A (39)
G (38)
a Method A: Pd/C (10%), molecular hydrogen, MeOH, r.t.; Method B: BCl3,
CH2Cl2, –78 °C to –20 °C; Method C: Pd(OH)2/C (20%), MeOH, cyclohexene,
reflux.
Coupling of the Nucleobase; General Procedure
To a solution/suspension of cyclopentenol 4 (1 equiv), PPh3 (1.5 equiv)
and the appropriate nucleobase (1.5 equiv) in MeCN was added DIAD
(1.5 equiv) dropwise. The reaction mixture was irradiated at 50 °C
(100 W) until full conversion was achieved. The nucleobases were
deprotected or further treated as indicated. Pyrimidines: The solvent
was removed under reduced pressure and the resulting residue was
dissolved in 1 M NaOH in MeOH and stirred at room temperature
overnight. The reaction was neutralized with 1 M HCl and concentrat-
ed in vacuo. The crude product was purified as indicated. Purines: The
solvent was removed under reduced pressure and the residue was pu-
rified as indicated. All coupling compounds contain impurities from
DIAD due to difficult purification.
All the presented nucleoside analogues were tested
against HIV-1 and HIV-2 in T-lymphocyte cell culture
(CEM/0 cells), but none of them showed anti-HIV activity
below the highest tested concentration of 10 μM. No cyto-
toxic side effects were observed up to 250 μM. The lack of
anti-HIV activity might also be a result of a lack of phos-
phorylation by the cellular kinases present in CEM cells. In
addition to possible anti-HIV activity, the new compounds
were also tested against RNA viruses (CHIKV, EV71, RSVA,
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

F
S. Weising et al.
Paper
Synthesis
(D)-1′,2′-cis-(6′-O-Benzyl)-cis-carba-d4T (1-{(1S,2R)-2-[(Benzyl-
oxy)methyl]cyclopent-3-en-1-yl}-5-methylpyrimidine-
2,4(1H,3H)-dione) (5a) and (D)-1′,2′-cis-(6′-O-Benzyl)-cis-carba-O2-
d4T (2-[{(1S,2S)-2-[(Benzyloxy)methyl]cyclopent-3-en-1-yl}oxy]-
5-methylpyrimidin-4(3H)-one) (5b)
6a
Yield: 669 mg (46%); colorless resin; Rf = 0.56 (CH2Cl2/MeOH, 95:5);
[α]D25 –217 (c 0.1, MeOH).
IR (neat): 3167, 3055, 2858, 1669, 1454, 1374, 1263, 1094, 735 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 9.18 (br s, 1 H, NH), 7.39–7.18 (m, 6 H,
H-Bn, H-6), 5.95–5.88 (m, 1 H, H-4′), 5.83–5.77 (m, 1 H, H-3′), 5.54 (d,
3J = 8.1 Hz, 1 H, H-5), 5.48–5.38 (m, 1 H, H-1′), 4.36 (s, 2 H, CH2Ph),
3.48–3.35 (m, 2 H, H-6′), 3.34–3.24 (m, 1 H, H-2), 2.94–2.82 (m, 1 H,
H-5a′), 2.58–2.47 (m, 1 H, H-5b′).
13C NMR (76 MHz, CDCl3): δ = 163.4 (Cq-4), 151.5 (Cq-2), 142.5 (C-6),
137.7 (Cq-Bn), 131.9 (C-4′), 129.7 (C-3′), 128.5 (2 × C-Bn), 127.9 (C-
Bn), 127.8 (2 × C-Bn), 101.4 (C-5), 73.5 (CH2-Ph), 68.2 (C-6′), 54.8 (C-
1′), 48.8 (C-2′), 38.1 (C-5′).
The reaction was carried out according to the general coupling proce-
dure with cyclopentenol 4 (0.460 mg, 2.25 mmol), PPh3 (887 mg, 3.38
mmol), N3-benzoylthymine (778 mg, 3.38 mmol) and DIAD (670 μL,
3.38 μmol) in MeCN (10 mL). Purification on silica gel (petroleum
ether/EtOAc, 1:2, petroleum ether/acetone, 2:1) afforded 5a and 5b.
5a
Yield: 262 mg (37%); colorless resin; Rf = 0.59 (CH2Cl2/MeOH, 95:5);
[α]D25 –139 (c 0.1, MeOH).
HRMS (ESI+): m/z [M + H]+ calcd for C17H19N2O3: 299.1390; found:
299.1391.
IR (neat): 3179, 3032, 2926, 2856, 1660, 1263, 1089, 735, 697 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.94 (br s, 1 H, NH), 7.38–7.18 (m, 5 H,
H-Bn), 7.04 (q, 4J = 1.2 Hz, 1 H, H-6), 5.96–5.89 (m, 1 H, H-4′), 5.86–
5.79 (m, 1 H, H-3′), 5.46–5.36 (m, 1 H, H-1′), 4.37–4.33 (m, 2 H,
CH2Ph), 3.45 (dd, 2J = 9.6 Hz, 3J = 6.3 Hz, 1 H, H-6a′), 3.37 (dd, 2J = 9.6
Hz, 3J = 4.8 Hz, 1 H, H-6b′), 3.33–3.27 (m, 1 H, H-2′), 2.94–2.81 (m, 1 H,
H-5a′), 2.60–2.48 (m, 1 H, H-5b′), 1.76 (d, 4J = 1.2 Hz, 3 H, CH3).
6b
Yield: 67.9 mg (5%); colorless resin; Rf = 0.48 (CH2Cl2/MeOH, 95:5).
IR (neat): 3062, 3030, 2857, 1663, 1590, 1553, 1307, 1288, 1093, 820,
730, 696 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 11.5 (br s, 1 H, NH), 7.71 (d, 3J = 6.6 Hz,
1 H, H-6), 7.34–7.18 (m, 5 H, H-Bn), 6.05 (d, 3J = 6.6 Hz, 1 H, H-5),
5.85–5.67 (m, 3 H, H-3′, H-4′, H-1′), 4.53–4.42 (m, 2 H, CH2Ph), 3.69
(dd, 2J = 9.2 Hz, 3J = 7.9 Hz, 1 H, H-6a′), 3.59 (dd, 2J = 9.2 Hz, 3J = 6.2 Hz,
1 H, H-6b′), 3.32–3.21 (m, 1 H, H-2′), 2.86–2.74 (m, 1 H, H-5a′), 2.64–
2.53 (m, 1 H, H-5b′).
13C NMR (76 MHz, CDCl3): δ = 165.4 (Cq-4), 157.5 (Cq-2), 155.0 (C-6),
138.4 (Cq-Bn), 130.4 (C-3′), 129.2 (C-4′), 128.4 (2 × C-Bn), 127.8 (2 × C-
Bn), 127.6 (C-Bn), 108.8 (C-5), 78.6 (C-1′), 73.3 (CH2Ph), 68.5 (C-6′),
48.7 (C-2′), 39.2 (C-5′).
13C NMR (101 MHz, CDCl3): δ = 163.5 (Cq-4), 151.3 (Cq-2), 138.5 (C-6),
137.8 (Cq-Bn), 132.0 (C-4′), 129.8 (C-3′), 128.5 (2 × C-Bn), 127.9 (C-
Bn), 127.7 (2 × C-Bn), 109.7 (C-5), 73.5 (CH2-Ph), 68.3 (C-6′), 54.6 (C-
1′), 48.9 (C-2′), 38.2 (C-5′), 12.6 (CH3).
HRMS (ESI+): m/z [M + H]+ calcd for C18H21N2O3: 313.1547; found:
313.1556.
5b
Yield: 56.4 mg (8%); colorless resin; Rf = 0.63 (CH2Cl2/MeOH, 95:5).
IR (neat): 3029, 2855, 1651, 1605, 1572, 1309, 1290, 1090, 1043, 733,
HRMS (ESI+): m/z [M + Na]+ calcd for C17H18N2NaO3: 321.1210; found:
321.1209.
696 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 10.7 (br s, 1 H, NH), 7.53 (q, 4J = 1.2 Hz,
1 H, H-6), 7.34–7.19 (m, 5 H, H-Bn), 5.84–5.65 (m, 3 H, H-3′, H-4′, H-
(D)-1′,2′-(6′-O-Benzyl)-cis-carba-d4C (4-Amino-1-{(1S,2R)-2-[(ben-
zyloxy)methyl]cyclopent-3-en-1-yl}pyrimidin-2(1H)-one) (7a)
2
3
1′), 4.47 (s, 2 H, CH2Ph), 3.69 (dd, J = 9.2 Hz, J = 7.6 Hz, 1 H, H-6a′),
3.58 (dd, 2J = 9.2 Hz, 3J = 6.3 Hz, 1 H, H-6b′), 3.31–3.20 (m, 1 H, H-2′),
2.86–2.74 (m, 1 H, H-5a′), 2.61–2.50 (m, 1 H, H-5b′), 1.95 (d, 4J = 1.2
Hz, 3 H, CH3).
To a solution of 1,2,4-triazole (421 mg, 6.09 mmol) in MeCN (5 mL)
was added freshly distilled POCl3 (123 μL, 1.31 mmol) dropwise at
0 °C. After stirring for 10 min, anhydrous Et3N (0.81 mL, 5.8 mmol)
was added and the resulting suspension was stirred for a further 20
min. Next, the uracil derivative 6a (202 mg, 677 μmol) dissolved in
MeCN (5 mL) was added and the reaction was stirred at room tem-
perature until full conversion. The reaction mixture was treated with
25% aqueous NH4OH solution (20 mL) for 48 h at room temperature.
After evaporation of the solvent, the crude product was purified on
silica gel (CH2Cl2/MeOH, 98:2 to 85:15) and on RP18 silica gel
(H2O/THF, 99:1 to 0:100, H2O/MeCN, 99:1 to 0:100) using automated
flash chromatography to afford 7a (149 mg, 74%) as a colorless foam.
13C NMR (76 MHz, CDCl3): δ = 164.9 (Cq-4), 155.5 (Cq-2), 151.0 (C-6),
138.3 (Cq-Bn), 130.3 (C-3′), 129.1 (C-4′), 128.3 (2 × C-Bn), 127.6 (2 × C-
Bn), 127.5 (C-Bn), 117.3 (C-5), 78.0 (C-1′), 73.2 (CH2Ph), 68.5 (C-6′),
48.5 (C-2′), 39.1 (C-5′), 12.4 (CH3).
HRMS (ESI–): m/z [M – H]+ calcd for C18H19N2O3: 311.1401; found:
311.1469.
(D)-1′,2′-cis-(6′-O-Benzyl)-cis-carba-d4U (1-{(1S,2R)-2-[(Benzy-
loxy)methyl]cyclopent-3-en-1-yl}pyrimidine-2,4(1H,3H)-dione)
(6a) and (D)-1′,2′-cis-(6′-O-Benzyl)-cis-carba-O2-d4U [2-[{(1S,2S)-2-
[(Benzyloxy)methyl]cyclopent-3-en-1-yl}oxy]pyrimidin-4(3H)-
one] (6b)
Rf = 0.21 (CH2Cl2/MeOH, 95:5); [α]D25 –365 (c 0.1, MeOH).
IR (neat): 3310, 3059, 2856, 1610, 1477, 1399, 1280, 1097, 786 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.34–7.16 (m, 6 H, H-6, H-Bn), 5.92–
The reaction was carried out according to the general coupling proce-
dure with cyclopentenol 4 (1.00 g, 4.90 mmol), PPh3 (1.93 g, 7.35
mmol), N3-benzoyluracil (1.59 g, 7.35 mmol) and DIAD (1.46 mL, 7.35
mmol) in MeCN (5 mL). Purification on silica gel (petroleum
ether/EtOAc, 1:2) and on RP18 silica gel (H2O/MeCN, 70:30 to 0:100)
afforded 6a and 6b.
3
5.86 (m, 1 H, H-3′), 5.84–5.79 (m, 1 H, H-4′), 5.71 (d, J = 7.5 Hz, 1 H,
H-5), 5.55–5.47 (m, 1 H, H-1′), 4.32–4.26 (m, 2 H, CH2Ph), 3.45 (dd, 2J =
9.2 Hz, 3J = 4.9 Hz, 1 H, H-6a′), 3.33–3.21 (m, 2 H, H-2′, H-6′), 2.86–
2.74 (m, 1 H, H-5a′), 2.55–2.45 (m, 1 H, H-5b′).
13C NMR (126 MHz, CDCl3): δ = 165.1 (Cq-4), 156.8 (Cq-2), 143.5 (C-6),
138.2 (Cq-Bn), 132.1 (C-4′), 129.5 (C-3′), 128.4 (2 × C-Bn), 127.7 (2 × C-
Bn), 127.6 (C-Bn), 94.0 (C-5), 73.3 (CH2Ph), 68.7 (C-6′), 55.5 (C-1′),
48.7 (C-2′), 38.2 (C-5′).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

G
S. Weising et al.
Paper
Synthesis
HRMS (ESI+): m/z [M + H]+ calcd for C17H20N3O2: 298.1550; found:
(D)-1′,2′-(6′-O-Benzyl)-cis-carba-d4A (9-{(1S,2R)-2-[(Benzy-
298.1558.
loxy)methyl]cyclopent-3-en-1-yl}-9H-purin-6-amine) (11)
In a closed microwave vessel, the chloropurine 8 (223 mg, 654 μmol)
was dissolved in MeCN (2 mL) and 25% NH4OH was added. The reac-
tion mixture was heated for 5 h at 70 °C (50 W). The solvents were
removed in vacuo and the crude residue was purified on silica gel
(CH2Cl2/MeOH, 19:1) to afford 11 (204 mg, 97%) as a colorless foam.
(D)-1′,2′-(6′-O-Benzyl)-cis-carba-O2-d4C (2-[{(1S,2S)-2-[(Benzy-
loxy)methyl]cyclopent-3-en-1-yl}oxy]pyrimidin-4-amine) (7b)
The reaction was carried out according to the general coupling proce-
dure with cyclopentenol 4 (1.37 g, 6.71 mmol), PPh3 (2.65 g, 10.1
mmol), N4-acetylcytosine (1.55 g, 10.1 mmol) and DIAD (2.0 mL, 10
mmol) in THF (50 mL). Purification on silica gel (petroleum
ether/EtOAc, 1:1 to 1:3) afforded 7b (908 mg, 45%) as a yellowish res-
in.
Rf = 0.38 (CH2Cl2/MeOH, 95:5); [α]D25 –193 (c 0.1, MeOH).
IR (neat): 3307, 3142, 2928, 2858, 1660, 1594, 1328, 1102, 652 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.35 (s, 1 H, H-2), 7.88 (s, 1 H, H-8),
7.29–7.18 (m, 3 H, H-Bn), 7.07–7.00 (m, 2 H, H-Bn), 6.09–6.04 (m, 1 H,
H-4′), 5.89–5.84 (m, 1 H, H-3′), 5.57 (br s, 2 H, NH2), 5.52–5.45 (m, 1 H,
H-1′), 4.14–4.03 (m, 2 H, CH2-Ph), 3.45–3.36 (m, 1 H, H-2′), 3.21–3.10
(m, 2 H, H-6′), 3.07–2.98 (m, 1 H, H-5a′), 2.96–2.87 (m, 1 H, H-5b′).
Rf = 0.40 (CH2Cl2/MeOH, 95:5).
IR (neat): 3325, 3169, 3061, 2857, 1626, 1587, 1555, 1400, 1292,
1072, 734, 696 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.96 (d, 3J = 5.7 Hz, 1 H, H-6), 7.33–7.17
(m, 5 H, H-Bn), 6.04 (d, 3J = 5.7 Hz, 1 H, H-5), 5.84–5.76 (m, 2 H, H-
3′,H-4′), 5.75–5.67 (m, 1 H, H-1′), 5.09 (br s, 2 H, NH2), 4.51–4.40 (m, 2
H, CH2Ph), 3.73 (dd, 2J = 9.1 Hz, 3J = 6.5 Hz, 1 H, H-6a′), 3.60 (dd, 2J = 9.1
Hz, 3J = 7.9 Hz, 1 H, H-6b′), 3.30–3.19 (m, 1 H, H-2′), 2.82–2.71 (m, 1 H,
H-5a′), 2.59–2.48 (m, 1 H, H-5b′).
13C NMR (76 MHz, CDCl3): δ = 165.0 (Cq-4), 164.9 (Cq-2), 157.0 (C-6),
138.8 (Cq-Bn), 131.3 (C-3′), 129.2 (C-4′), 128.3 (2 × C-Bn), 127.6 (2 × C-
Bn), 127.4 (C-Bn), 99.4 (C-5), 76.6 (C-1′), 73.3 (CH2Ph), 69.6 (C-6′),
48.5 (C-2′), 39.2 (C-5′).
13C NMR (151 MHz, CDCl3): δ = 155.4 (Cq-6), 152.8 (C-2), 150.5 (Cq-4),
139.6 (C-8), 137.5 (Cq-Bn), 131.2 (C-3′), 130.0 (C-4′), 128.2 (2 × C-Bn),
127.5 (C-Bn), 127.4 (2 × C-Bn), 119.0 (C-5), 73.1 (CH2-Ph), 68.3 (C-6′),
54.3 (C-1′), 49.4 (C-2′), 39.0 (C-5′).
HRMS (ESI+): m/z [M + H]+ calcd for C18H20N5O: 322.1662; found:
322.1661.
(D)-1′,2′-(6′-O-Benzyl)-cis-carba-6-chloro-d4G (9-{(1S,2R)-2-[(Ben-
zyloxy)methyl]cyclopent-3-en-1-yl}-6-chloro-9H-purin-2-amine)
(9)
HRMS (ESI+): m/z [M + H]+ calcd for C17H20N3O2: 298.1550; found:
298.1565.
The reaction was carried out according to the general coupling proce-
dure with cyclopentenol 4 (1.10 g, 5.39 mmol), PPh3 (2.12 g, 8.09
mmol), 2-amino-6-chloropurine (1.37 g, 8.09 mmol) and DIAD (1.60
mL, 8.09 mmol) in MeCN (43 mL). Purification on silica gel (petro-
leum ether/EtOAc, 1:2 to 1:3, CH2Cl2/MeOH, 19:1) afforded 9 (0.726 g,
40%) as a colorless resin. A yield of 59% was obtained by using THF as
the solvent.
(D)-1′,2′-(6′-O-Benzyl)-cis-carba-6-chloro-d4A (9-{(1S,2R)-2-[(Ben-
zyloxy)methyl]cyclopent-3-en-1-yl}-6-chloro-9H-purine) (8)
The reaction was carried out according to the general coupling proce-
dure with cyclopentenol 4 (1.52 g, 7.44 mmol), PPh3 (2.94 g, 11.2
mmol), 6-chloropurine (1.73 g, 11.2 mmol) and DIAD (2.22 mL, 11.2
mmol) in MeCN (20 mL). Purification on silica gel (petroleum
ether/EtOAc, 1:1, CH2Cl2/MeCN, 9:1) afforded 8 (1.15 g, 45%) as a col-
orless resin. A yield of 60% was obtained by using THF as the solvent.
Rf = 0.41 (petroleum ether/EtOAc, 1:2); [α]D25 –219 (c 0.1, MeOH).
IR (neat): 3313, 3195, 2856, 1604, 1558, 1456, 1402, 1216, 1088, 901,
697 cm–1
.
1H NMR (500 MHz, CDCl3): δ = 7.88 (s, 1 H, H-8), 7.31–7.19 (m, 3 H, H-
Bn), 7.06–6.98 (m, 2 H, H-Bn), 6.07–6.02 (m, 1 H, H-4′), 5.84–5.79 (m,
1 H, H-3′), 5.37–5.31 (m, 1 H, H-1′), 5.20 (br s, 2 H, NH2), 4.16 (d, 2J =
11.6 Hz, 1 H, CHHPh), 4.02 (d, 2J = 11.6 Hz, 1 H, CHHPh), 3.43–3.36 (m,
1 H, H-2′), 3.27 (dd, 2J = 9.7 Hz, 3J = 4.7 Hz, 1 H, H-6a′), 3.12 (dd, 2J = 9.7
Hz, 3J = 7.7 Hz, 1 H, H-6b′), 3.04–2.96 (m, 1 H, H-5a′), 2.87–2.80 (m, 1
H, H-5b′).
Rf = 0.50 (petroleum ether/EtOAc, 1:2); [α]D25 –181 (c 0.1, MeOH).
IR (neat): 3062, 3030, 2857, 1589, 1556, 1336, 1205, 1088, 949, 724,
697 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.67 (s, 1 H, H-2), 8.22 (s, 1 H, H-8),
7.23–7.19 (m, 3 H, H-Bn), 6.93–6.89 (m, 2 H, H-Bn), 6.10–6.05 (m, 1 H,
2
H-4′), 5.84–5.81 (m, 1 H, H-3′), 5.58–5.53 (m, 1 H, H-1′), 4.06 (d, J =
11.7 Hz, 1 H, CHHPh), 3.94 (d, 2J = 11.7 Hz, 1 H, CHHPh), 3.47–3.41 (m,
1 H, H-2′), 3.20 (dd, 2J = 9.8 Hz, 3J = 4.4 Hz, 1 H, H-6a′), 3.12 (dd, 2J = 9.8
Hz, 3J = 7.4 Hz, 1 H, H-6b′), 3.08–3.02 (m, 1 H, H-5a′), 2.97–2.91 (m, 1
H, H-5b′).
13C NMR (126 MHz, CDCl3): δ = 158.8 (Cq-6), 153.9 (Cq-4), 151.0 (C-2),
141.7 (C-8), 137.4 (Cq-Bn), 131.1 (C-3′), 130.4 (C-4′), 128.4 (2 × C-Bn),
127.8 (C-Bn), 127.7 (2 × C-Bn), 124.5 (Cq-5), 73.4 (CH2Ph), 68.3 (C-6′),
54.6 (C-1′), 49.6 (C-2′), 39.2 (C-5′).
13C NMR (151 MHz, CDCl3): δ = 152.3 (Cq-4), 151.9 (C-2), 150.8 (Cq-6),
144.5 (C-8), 137.1 (Cq-Bn), 131.0 (C-3′), 130.9 (Cq-5), 130.3 (C-4′),
128.4 (2 × C-Bn), 127.8 (C-Bn), 127.6 (2 × C-Bn), 73.3 (CH2Ph), 68.1 (C-
6′), 55.3 (C-1′), 49.6 (C-2′), 39.0 (C-5′).
HRMS (ESI+): m/z [M + H]+ calcd for C18H18ClN4O: 341.1164; found:
341.1164.
HRMS (ESI+): m/z [M + H]+ calcd for C18H19ClN5O: 356.1273; found:
356.1278.
(D)-1′,2′-(6′-O-Benzyl)-cis-carba-d4G (2-Amino-9-{(1S,2R)-2-[(ben-
zyloxy)methyl]cyclopent-3-en-1-yl}-1,9-dihydro-6H-purin-6-one)
(10)
Mitsunobu
The reaction was carried out according to the general coupling proce-
dure with cyclopentenol 4 (239 mg, 1.17 mmol), PPh3 (461 mg, 1.76
mmol), 2-amino-6-chloropurine (422 mg, 1.76 mmol) and DIAD (349
μL, 1.76 mmol) in MeCN (6 mL). The residue was dissolved in formic
acid (8 mL) and heated at reflux for 6 h. After evaporation of the sol-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

H
S. Weising et al.
Paper
Synthesis
vent, the residue was taken up in 7 M NH3 in MeOH (10 mL) and
stirred overnight at room temperature. Purification on silica gel (CH2-
Cl2/MeOH, 9:1) and freeze-drying (H2O/MeCN, 1:1) afforded 10 (80.8
mg, 20%) as a colorless cotton. A yield of 52% was obtained by using
THF as the solvent.
(D)-1′,2′-cis-carba-d4T (1-[(1S,2R)-2-(Hydroxymethyl)cyclopent-3-
en-1-yl]-5-methylpyrimidine-2,4(1H,3H)-dione) (12)
Method A
The reaction was carried out according to the general procedure with
5a (149 mg, 477 μmol) and ZnCl2 (584 mg, 4.28 mmol) in Ac2O/AcOH
(5:1, 12 mL). Purification on silica gel (CH2Cl2/MeOH, 19:1) afforded
12 (77.8 mg, 74%) as a colorless cotton.
Substitution
The chloropurine 9 (220 mg, 618 μmol) was dissolved in 0.5 M aque-
ous NaOH solution (10 mL). The reaction mixture was heated at reflux
until full conversion. After evaporation of all the volatiles, the residue
was purified on RP18 silica gel by automated flash chromatography
(H2O/THF, 99:1 to 0:100) and freeze-dried (H2O/MeCN, 1:1) to afford
10 (156 mg, 75%) as a colorless cotton.
Method B
The reaction was carried out according to the general procedure with
5a (1.08 g, 3.46 mmol) and 1 M BCl3 in CH2Cl2 (17.3 mL, 17.3 mmol) in
CH2Cl2 (50 mL). Purification on silica gel (CH2Cl2/MeOH, 19:1) and on
RP18 silica gel with automated flash chromatography (H2O/MeCN,
99:1 to 0:100) and freeze-drying (H2O/MeCN, 1:1) afforded 12 (554
mg, 72%) as a colorless cotton.
Rf = 0.21 (CH2Cl2/MeOH, 95:5); [α]D25 –190 (c 0.1, MeOH).
IR (neat): 3324, 3175, 2851, 2723, 1674, 1619, 1568, 1479, 1385,
1175, 1074, 717, 680 cm–1
.
Rf = 0.72 (CH2Cl2/MeOH, 85:15); [α]D25 –333 (c 0.1, MeOH).
1H NMR (600 MHz, CDCl3): δ = 10.6 (br s, 1 H, NH), 7.64 (s, 1 H, H-8),
7.29 (m, 3 H, H-Bn), 7.10–7.05 (m, 2 H, H-Bn), 6.44 (br s, 2 H, NH2),
6.02–5.97 (m, 1 H, H-4′), 5.83–5.77 (m, 1 H, H-3′), 5.12–5.04 (m, 1 H,
H-1′), 4.16 (d, 2J = 11.9 Hz, 1 H, CHHPh), 4.08 (d, 2J = 11.9 Hz, 1 H, CH-
HPh), 3.24–3.12 (m, 3 H, H-2′, H-6′), 2.94–2.80 (m, 2 H, H-5′).
13C NMR (151 MHz, CDCl3): δ = 157.1 (Cq-6), 153.6 (Cq-4), 151.6 (Cq-
2), 138.0 (Cq-Bn), 135.7 (C-8), 130.8 (C-3′), 130.4 (C-4′), 128.0 (2 × C-
Bn), 127.2 (3 × C-Bn), 116.2 (C-5), 72.1 (CH2Ph), 68.5 (C-6′), 53.5 (C-
1′), 48.2 (C-2′), 37.4 (C-5′).
IR (neat): 3448, 3153, 2964, 2897, 1661, 1472, 1274, 1122, 1043, 839,
713, 655 cm–1
1H NMR (400 MHz, DMSO-d6): δ = 11.2 (br s, 1 H, NH), 7.28 (q, 4J = 1.2
Hz, 1 H, H-6), 5.94–5.87 (m, 1 H, H-4′), 5.82–5.75 (m, 1 H, H-3′), 5.22–
5.13 (m, 1 H, H-1′), 4.51 (t, 3J = 4.9 Hz, 1 H, -OH), 3.33–3.19 (m, 2 H, H-
6′), 3.03–2.94 (m, 1 H, H-2′), 2.78–2.69 (m, 1 H, H-5a′), 2.64–2.56 (m,
1 H, H-5b′), 1.74 (d, 4J = 1.2 Hz, 3 H, CH3).
13C NMR (101 MHz, DMSO-d6): δ = 163.8 (Cq-4), 151.3 (Cq-2), 138.4
(C-6), 131.7 (C-3′), 129.6 (C-4′), 108.0 (Cq-5), 59.6 (C-6′), 53.9 (C-1′),
50.2 (C-2′), 36.6 (C-5′), 12.2 (CH3).
HRMS (ESI+): m/z [M + H]+ calcd for C18H20N5O2: 338.1612; found:
338.1620.
HRMS (ESI+): m/z [M + H]+ calcd for C11H15N2O3: 223.1077; found:
223.1077.
Debenzylation Reactions; General Procedures
Method A
(D)-1′,2′-cis-carba-d4U (1-[(1S,2R)-2-(Hydroxymethyl)cyclopent-3-
en-1-yl]pyrimidine-2,4(1H,3H)-dione) (13)
ZnCl2 was heated under a nitrogen atmosphere until it became a clear
liquid. After cooling to room temperature, Ac2O/AcOH (5:1) was add-
ed. The resulting solution was added to a solution of the appropriate
nucleoside in Ac2O/AcOH (5:1). After full conversion, H2O was added,
and the aqueous phase was extracted three times with CH2Cl2. The
combined organic layers were washed carefully with saturated aque-
ous NaHCO3, H2O and brine. After drying over anhydrous Na2SO4, the
solvent was removed under reduced pressure. The residue was treat-
ed with NaOH (1%) in MeOH overnight. After neutralization with 1 M
HCl and coevaporation with toluene, the crude product was purified
as indicated.
Method A
The reaction was carried out according to the general procedure with
6a (225 mg, 754 μmol) and ZnCl2 (924 mg, 6.78 mmol) in Ac2O/AcOH
(5:1, 12 mL). Purification on silica gel (CH2Cl2/MeOH, 19:1) and
freeze-drying (H2O/MeCN, 1:1) afforded 13 (77.7 mg, 50%) as a color-
less cotton.
Method B
The reaction was carried out according to the general procedure with
6a (149 mg, 499 μmol) and 1 M BCl3 in CH2Cl2 (2.5 mL, 2.5 mmol) in
CH2Cl2 (6 mL). Purification on RP18 silica gel with automated flash
chromatography (H2O/MeCN, 99:1 to 0:100) and freeze-drying
(H2O/MeCN, 1:1) afforded 13 (95.0 mg, 91%) as a colorless cotton.
Method B
The appropriate nucleoside analogue was dissolved in anhydrous
CH2Cl2 and cooled to –78 °C. Next, BCl3 (1 M) in CH2Cl2 was added
dropwise and the resulting suspension slowly warmed to –20 °C. Af-
ter full conversion, the reaction was cooled to –78 °C and MeOH was
added. The reaction mixture was warmed to room temperature and
all the volatiles were removed in vacuo. The residue was coevaporated
three times with MeOH and the crude product was purified as indi-
cated.
Rf = 0.63 (CH2Cl2/MeOH, 85:15); [α]D25 –282 (c 0.1, MeOH).
IR (neat): 3390, 3173, 3052, 2874, 1658, 1460, 1376, 1265, 1024, 806,
549 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.2 (br s, 1 H, -NH), 7.43 (d, 3J = 8.1
Hz, 1 H, H-6), 5.94–5.86 (m, 1 H, H-4′), 5.81–5.75 (m, 1 H, H-3′), 5.50
(d, 3J = 8.1 Hz, 1 H, H-5), 5.24–5.13 (m, 1 H, H-1′), 4.55 (t, 3J = 4.9 Hz, 1
H, -OH), 3.33–3.21 (m, 2 H, H-6′), 3.04–2.95 (m, 1 H, H-2′), 2.80–2.70
(m, 1 H, H-5a′), 2.61–2.53 (m, 1 H, H-5b′).
13C NMR (101 MHz, DMSO-d6): δ = 163.2 (Cq-4), 151.4 (Cq-2), 142.9
(C-6), 131.6 (C-3′), 129.7 (C-4′), 100.5 (C-5), 59.4 (C-6′), 54.2 (C-1′),
50.2 (C-2′), 36.8 (C-5′).
Method C
The appropriate nucleoside analogue was dissolved in anhydrous
CH2Cl2 and cooled to 0 °C. Next, 1 M TMSI was added and the result-
ing reaction mixture was stirred at room temperature until full con-
version.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

I
S. Weising et al.
Paper
Synthesis
HRMS (ESI+): m/z [M + H]+ calcd for C10H13N2O3: 209.0921; found:
209.0921.
(D)-1′,2′-cis-carba-d4G (2-Amino-9-[(1S,2R)-2-(hydroxymethyl)cy-
clopent-3-en-1-yl]-1,9-dihydro-6H-purin-6-one) (16)
(D)-1′,2′-cis-carba-d4C (4-Amino-1-[(1S,2R)-2-(hydroxymethyl)cy-
clopent-3-en-1-yl]pyrimidin-2(1H)-one) (14)
Method B
The reaction was carried out according to the general procedure with
10 (80.2 mg, 238 μmol) and 1 M BCl3 in CH2Cl2 (1.78 mL) in CH2Cl2 (5
mL). In this case, the reaction was quenched with saturated NaHCO3
solution (5 mL) and the solvent was evaporated. Purification on silica
gel (CH2Cl2/MeOH, 80:20) and freeze-drying (H2O/MeCN, 1:1) afford-
ed 16 (58.6 mg, 100%) as a colorless cotton.
Method B
The reaction was carried out according to the general procedure with
7a (60.5 g, 203 μmol) and 1 M BCl3 in CH2Cl2 (1.0 mL, 1.0 mmol) in
CH2Cl2 (5 mL). Purification on RP18 silica gel with automated flash
chromatography (H2O/MeCN, 99:1 to 0:100) and freeze-drying
(H2O/MeCN, 1:1) afforded 14 (42.0 mg, 100%) as a colorless cotton.
Method C
Rf = 0.30 (CH2Cl2/MeOH, 85:15); [α]D25 –351 (c 0.1, MeOH).
IR (neat): 3324, 3180, 2857, 1637, 1480, 1399, 1283, 1025, 789 cm–1
The reaction was carried out according to the general procedure with
10 (49.1 mg, 146 μmol) and TMSI (100 μL, 700 μmol) in CH2Cl2 (20
mL). In this case, the reaction was quenched with saturated Na2S2O3
solution (0.5 mL) and the solvent was evaporated. Purification on sili-
ca gel (CH2Cl2/MeOH, 80:20) and freeze-drying (H2O/MeCN, 1:1) af-
forded 16 (29.5 mg, 82%) as a colorless cotton.
.
1H NMR (400 MHz, DMSO-d6): δ = 7.39 (d, 3J = 7.3 Hz, 1 H, H-6), 7.11–
6.88 (m, 2 H, NH2), 5.93–5.87 (m, 1 H, H-4′), 5.83–5.77 (m, 1 H, H-3′),
5.64 (d, 3J = 7.3 Hz, 1 H, H-5), 5.26–5.17 (m, 1 H, H-1′), 4.45 (br s, 1 H,
2
3
2
OH), 3.24 (dd, J = 10.5 Hz, J = 5.7 Hz, 1 H, H-6a′), 3.08 (dd, J = 10.5
Hz, 3J = 7.3 Hz, 1 H, H-6b′), 3.02–2.94 (m, 1 H, H-2′), 2.76–2.65 (m, 1 H,
H-5a′), 2.56–2.47 (m, 1 H, H-5b′).
Rf = 0.30 (CH2Cl2/MeOH, 85:15); [α]D25 –258 (c 0.1, MeOH).
IR (neat): 3370, 3185, 2870, 2728, 1679, 1629, 1603, 1386, 1175, 783,
577 cm–1
.
13C NMR (101 MHz, DMSO-d6): δ = 165.2 (Cq-4), 156.3 (Cq-2), 143.1
(C-6), 132.0 (C-3′), 129.5 (C-4′), 93.1 (C-5), 59.8 (C-6′), 54.8 (C-1′), 50.7
(C-2′), 37.0 (C-5′).
HRMS (ESI+): m/z [M + H]+ calcd for C10H14N3O2: 208.1081; found:
208.1070.
1H NMR (400 MHz, DMSO-d6): δ = 10.6 (br s, 1 H, NH), 7.61 (s, 1 H, H-
8), 6.44 (br s, 2 H, NH2), 6.01–5.95 (m, 1 H, H-4′), 5.88–5.83 (m, 1 H, H-
3
3′), 5.04–4.96 (m, 1 H, H-1′), 4.43 (t, J = 4.7 Hz, 1 H, -OH), 3.13–3.06
(m, 1 H, H-6a′), 3.03–2.92 (m, 2 H, H-2′, H-6b′), 2.89–2.77 (m, 2 H, H-
5′).
13C NMR (101 MHz, DMSO-d6): δ = 156.9 (Cq-6), 153.5 (Cq-4), 151.5
(Cq-2), 136.0 (C-8), 131.6 (C-3′), 129.8 (C-4′), 116.1 (Cq-5), 59.9 (C-6′),
53.6 (C-1′), 50.6 (C-2′), 37.5 (C-5′).
(D)-1′,2′-cis-carba-d4A (9-[(1S,2R)-2-(Hydroxymethyl)cyclopent-3-
en-1-yl]-9H-purin-6-amine) (15)
HRMS (ESI+): m/z [M + H]+ calcd for C11H14N5O2: 248.1142; found:
248.1147.
Method A
The reaction was carried out according to the general procedure with
11 (93.0 mg, 289 μmol) and ZnCl2 (355 mg, 2.60 mmol) in Ac2O/AcOH
(5:1, 12 mL). Purification on silica gel with automated flash chroma-
tography (CH2Cl2/MeOH, 19:1 to 85:15) and freeze-drying
(H2O/MeCN, 1:1) afforded 12 (47.8 mg, 71%) as a colorless cotton.
Benzyl Ether Hydrogenolysis and Double Bond Reduction; General
Procedure
The appropriate protected nucleoside was dissolved in anhydrous
MeOH and a catalytic amount of Pd/C (10%) was added. The reaction
mixture was stirred at room temperature under a hydrogen atmo-
sphere until full conversion. The suspension was filtered over Celite,®
the solvent evaporated and the crude residue purified as indicated.
Method B
The reaction was carried out according to the general debenzylation
procedure above with 11 (812 mg, 2.53 mmol) and 1 M BCl3 (CH2Cl2,
12.6 mL, 12.6 mmol) in CH2Cl2 (12.5 mL). Purification on silica gel
(CH2Cl2/MeOH, 9:1) and freeze-drying (H2O/MeCN, 1:1) afforded 15
(515 mg, 88%) as a colorless cotton.
(D)-1′,2′-cis-carba-ddT (1-[(1S,2R)-2-(Hydroxymethyl)cyclopen-
tyl]-5-methylpyrimidine-2,4(1H,3H)-dione) (17)
The reaction was carried out according to the general procedure
above with 5a (84.5 mg, 271 μmol) in MeOH (4 mL). Purification on
silica gel (CH2Cl2/MeOH, 19:1) and freeze-drying (H2O/MeCN, 1:1) af-
forded 17 (41.2 mg, 68%) as a colorless cotton.
Rf = 0.50 (CH2Cl2/MeOH, 85:15); [α]D25 –258 (c 0.1, MeOH).
IR (neat): 3390, 3098, 2957, 2921, 1673, 1604, 1302, 1026, 711 cm–1
1H NMR (600 MHz, CD3OD): δ = 8.21 (s, 1 H, H-2), 8.15 (s, 1 H, H-8),
6.12–6.08 (m, 1 H, H-4′), 5.91–5.87 (m, 1 H, H-3′), 5.41–5.37 (m, 1 H,
H-1′), 3.30–3.27 (m, 1 H, H-6a′), 3.27–3.22 (m, 1 H, H-2′), 3.14 (dd, 2J =
10.6 Hz, 3J = 5.6 Hz, 1 H, H-6b′), 3.06–2.97 (m, 2 H, H-5′).
.
Rf = 0.69 (CH2Cl2/MeOH, 85:15); [α]D25 –110 (c 0.1, MeOH).
IR (neat): 3447, 3031, 2964, 2899, 1652, 1475, 1273, 1043, 841 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 11.2 (br s, 1 H, NH), 7.43 (q, 4J = 1.3
Hz, 1 H, H-6), 4.75–4.66 (m, 1 H, H-1′), 4.38 (t, 1 H, -OH), 3.26–3.12
(m, 2 H, H-6′), 2.30–2.20 (m, 1 H, H-2′), 1.98–1.71 (m, 7 H, H-5′, H-4a′,
H-3a′, CH3), 1.58–1.45 (m, 2 H, H-3b′, H-4b′).
13C NMR (101 MHz, DMSO-d6): δ = 163.9 (Cq-4), 151.5 (Cq-2), 139.1
(C-6), 107.6 (Cq-5), 60.7 (C-6′), 57.4 (C-1′), 42.2 (C-2′), 28.8 (C-5′), 27.3
(C-3′), 22.3 (C-4′), 12.2 (CH3).
13C NMR (151 MHz, CD3OD): δ = 157.3 (C-6), 153.6 (C-2), 151.2 (C-4),
141.6 (C-8), 132.1 (C-3′), 131.4 (C-4′), 119.7 (C-5), 61.3 (C-6′), 56.4 (C-
1′), 52.4 (C-2′), 39.1 (C-5′).
HRMS (ESI+): m/z [M + H]+ calcd for C11H14N5O: 232.1193; found:
232.1193.
HRMS (ESI+): m/z [M + H]+ calcd for C11H17N2O3: 225.1236; found:
225.1234.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

J
S. Weising et al.
Paper
Synthesis
(D)-1′,2′-cis-carba-ddU (1-[(1S,2R)-2-(Hydroxymethyl)cyclopen-
tyl)]pyrimidine-2,4(1H,3H)-dione) (18)
IR (neat): 3361, 3110, 2949, 1670, 1604, 1568, 1412, 1301, 1030, 697,
613 cm–1
.
1H NMR (500 MHz, DMSO-d6): δ = 8.13 (s, 1 H, H-2), 8.08 (s, 1 H, H-8),
7.20 (br s, 2 H, NH2), 5.00–4.91 (m, 1 H, H-1′), 4.41 (t, 3J = 5.1 Hz, 1 H, -
OH), 3.01–2.90 (m, 2 H, H-6′), 2.41–2.31 (m, 1 H, H-2′), 2.27–2.17 (m,
2 H, H-5′), 2.05–1.96 (m, 1 H, H-4a′), 1.89–1.81 (m, 1 H, H-3a′), 1.74–
1.57 (m, 2 H, H-4b′, H-3b′).
The reaction was carried out according to the general procedure
above with 6a (274 mg, 918 μmol) in MeOH (15 mL). Purification on
silica gel (CH2Cl2/MeOH, 9:1) and freeze-drying (H2O/MeCN, 1:1) af-
forded 18 (153 mg, 79%) as a colorless cotton.
Rf = 0.66 (CH2Cl2/MeOH, 85:15); [α]D25 –162 (c 0.1, MeOH).
13C NMR (126 MHz, DMSO-d6): δ = 156.0 (C-6), 152.1 (C-2), 149.9 (C-
4), 140.1 (C-8), 118.6 (C-5), 60.5 (C-6′), 56.2 (C-1′), 45.3 (C-2′), 30.3 (C-
5′), 27.2 (C-3′), 22.3 (C-4′).
HRMS (ESI+): m/z [M + H]+ calcd for C11H16N5O: 234.1349; found:
234.1349.
IR (neat): 3351, 2955, 2823, 1679, 1379, 1273, 1041, 802, 762, 558
cm–1
.
1H NMR (600 MHz, DMSO-d6): δ = 11.1 (br s, 1 H, NH), 7.55 (d, 3J = 8.0
Hz, 1 H, H-6), 5.47 (d, 3J = 8.0 Hz, 1 H, H-5), 4.74–4.69 (m, 1 H, H-1′),
4.45 (br s, 1 H, -OH), 3.22 (dd, 2J = 10.8 Hz, 3J = 6.4 Hz, 1 H, H-6a′), 3.17
(dd, 2J = 10.8 Hz, 3J = 6.1 Hz, 1 H, H-6b′), 2.30–2.22 (m, 1 H, H-2′),
1.94–1.88 (m, 2 H, H-5′), 1.84–1.74 (m, 2 H, H-3a′, H-4a′), 1.57–1.45
(m, 2 H, H-3b′, H-4b′).
(D)-1′,2′-cis-carba-ddG (2-Amino-9-[(1S,2R)-2-(Hydroxymethyl)cy-
clopentyl]-1,9-dihydro-6H-purin-6-one) (21)
13C NMR (101 MHz, DMSO-d6): δ = 163.7 (Cq-4), 151.9 (Cq-2), 143.3
(C-6), 100.1 (C-5), 60.7 (C-6′), 57.6 (C-1′), 42.5 (C-2′), 28.8 (C-5′), 27.1
(C-3′), 22.1 (C-4′).
HRMS (ESI+): m/z [M + H]+ calcd for C10H15N2O3: 211.1077; found:
211.1081.
The reaction was carried out according to the general procedure
above with 10 (63.7 mg, 189 μmol) in MeOH/H2O (4:1, 15 mL). Purifi-
cation on silica gel (CH2Cl2/MeOH, 85:15) and on RP18 silica gel
(H2O/MeCN, 98:2 to 0:100) and freeze-drying (H2O/MeCN, 1:1) af-
forded 21 (41.2 mg, 87%) as a colorless cotton.
Rf = 0.36 (CH2Cl2/MeOH, 85:15); [α]D25 –108 (c 0.1, MeOH).
(D)-1′,2′-cis-carba-ddC (4-Amino-1-[(1S,2R)-2-(hydroxymethyl)cy-
clopentyl]pyrimidin-2(1H)-one) (19)
IR (neat): 3326, 3162, 2929, 2868, 2734, 1693, 1607, 1528, 1381,
1178, 1024, 779, 510 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.5 (br s, 1 H, NH), 7.65 (s, 1 H, H-
8), 6.44 (br s, 2 H, NH2), 4.75–4.65 (m, 1 H, H-1′), 4.41 (t, 3J = 5.3 Hz, 1
H, -OH), 3.03–2.95 (m, 2 H, H-6′), 2.34–2.22 (m, 1 H, H-2′), 2.21–2.03
(m, 2 H, H-5′), 2.01–1.89 (m, 1 H, H-4a′), 1.87–1.76 (m, 1 H, H-3a′),
1.72–1.50 (m, 2 H, H-4b′, H-3b′).
13C NMR (101 MHz, DMSO-d6): δ = 156.9 (Cq-6), 153.4 (Cq-2), 151.4
(Cq-4), 136.3 (C-8), 116.2 (Cq-5), 60.5 (C-6′), 55.6 (C-1′), 45.2 (C-2′),
30.3 (C-5′), 27.0 (C-3′), 22.0 (C-4′).
The uridine derivative 6a (101 mg, 480 μmol) was dissolved in
Ac2O/pyridine (1:3, 10 mL) and stirred for 24 h at room temperature.
All the volatiles were evaporated, and the residue was coevaporated
three times with toluene and once with CH2Cl2. The residue was puri-
fied on silica gel (CH2Cl2/MeOH, 99:1 to 90:10) to afford acetylated 18
(106 mg). Further conversion was carried out according to the above
procedure for 7a with 1,2,4-triazole (261 mg, 3.78 mmol), POCl3 (75.6
μL, 811 μmol) and Et3N (0.50 mL, 3.6 mmol) in MeCN (5 + 5 mL). Next,
25% aqueous NH4OH solution (10 mL) was added. Purification on sili-
ca gel (CH2Cl2/MeOH, 95:5 to 80:20) and on RP18 silica gel with auto-
mated flash chromatography (H2O/MeCN, 99:1 to 0:100) and freeze-
drying (H2O/MeCN, 1:1) afforded 19 (63.5 mg, 64% over two steps) as
a colorless cotton.
HRMS (ESI+): m/z [M + H]+ calcd for C11H16N5O2: 250.1299; found:
250.1301.
Asymmetric Dihydroxylation; General Procedure
Rf = 0.36 (CH2Cl2/MeOH, 85:15); [α]D25 –221 (c 0.1, MeOH).
The cyclopentene derivative was dissolved in t-BuOH/H2O (2:1 or 1:1)
and AD-mix β (1.4 g per mmol) and methanesulfonamide (1 equiv)
were added. The reaction mixture was stirred at room temperature
until full conversion of the starting material. The reaction was
quenched by the addition of saturated aqueous NaHSO3 solution and
the mixture was stirred for 30 min at room temperature. All the vola-
tiles were removed in vacuo and the residue purified as indicated.
IR (neat): 3325, 3185, 2949, 2871, 1634, 1600, 1474, 1283, 1035, 788,
596 cm–1
.
1H NMR (300 MHz, DMSO-d6): δ = 7.46 (d, 3J = 7.4 Hz, 1 H, H-6), 7.00
(br s, 2 H, NH2), 5.67 (d, 3J = 7.4 Hz, 1 H, H-5), 4.82–4.70 (m, 1 H, H-1′),
4.44 (t, 3J = 5.4 Hz, 1 H, OH), 3.14–3.02 (m, 2 H, H-6′), 2.33–2.17 (m, 1
H, H-2′), 2.00–1.68 (m, 4 H, H-5′, H-4a′, H-3a′), 1.65–1.36 (m, 2 H, H-
4b′, H-3b′).
13C NMR (76 MHz, DMSO-d6): δ = 165.3 (Cq-4), 156.7 (Cq-2), 143.5 (C-
6), 93.0 (C-5), 60.6 (C-6′), 58.1 (C-1′), 43.9 (C-2′), 29.1 (C-5′), 26.7 (C-
3′), 21.9 (C-4′).
(D)-1′,2′-cis-(6′-O-Benzyl)-carba-ribo-thymidine (1-{(1S,2R,3R,4S)-
2-[(Benzyloxy)methyl]-3,4-dihydroxycyclopentyl}-5-methylpy-
rimidine-2,4(1H,3H)-dione) (22)
The reaction was carried out according to the general dihydroxylation
procedure with 5a (50.0 mg, 160 μmol), AD-mix β (224 mg) and
methanesulfonamide (15.2 mg, 160 μmol) in t-BuOH/H2O (2:1, 6 mL).
Purification on RP18 silica gel (H2O/MeCN, 97:3 to 0:100) and freeze-
drying (H2O/MeCN, 1:1) afforded 22 (49.5 mg, 89%) as a colorless cot-
ton. The use of AD-mix α led to an 86% yield.
HRMS (ESI+): m/z [M + H]+ calcd for C10H16N3O2: 210.1237; found:
210.1234.
(D)-1′,2′-cis-carba-ddA (9-[(1S,2R)-2-(Hydroxymethyl)cyclopen-
tyl]-9H-purin-6-amine) (20)
Rf = 0.68 (CH2Cl2/MeOH, 85:15); [α]D25 –55 (c 0.1, MeOH).
The reaction was carried out according to the general procedure
above with 11 (79.9 mg, 249 μmol) in MeOH (4 mL). Purification on
silica gel (CH2Cl2/MeOH, 9:1) and freeze-drying (H2O/MeCN, 1:1) af-
forded 20 (46.2 mg, 80%) as a colorless cotton.
The IR and NMR analytical data are identical to those reported earli-
er.10
HRMS (ESI+): m/z [M + H]+ calcd for C18H23N2O5: 347.1601; found:
Rf = 0.60 (CH2Cl2/MeOH, 85:15); [α]D25 –73 (c 0.1, MeOH).
347.1618.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

K
S. Weising et al.
Paper
Synthesis
(D)-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) (23)
Rf = 0.26 (CH2Cl2/MeOH, 85:15); [α]D25 69 (c 0.1, MeOH).
The IR and NMR analytical data are identical to those reported earli-
er.10
The reaction was carried out according to the general dihydroxylation
procedure with 6a (50 mg, 168 μmol), AD-mix β (235 mg) and meth-
anesulfonamide (16.0 mg, 168 μmol) in t-BuOH/H2O (2:1, 6 mL). Puri-
fication on RP18 silica gel (H2O/MeCN, 97:3 to 0:100) and freeze-dry-
ing (H2O/MeCN, 1:1) afforded 23 (53.2 mg, 95%) as a colorless cotton.
The use of AD-mix α led to an 83% yield.
HRMS (ESI+): m/z [M + H]+ calcd for C18H22N5O4: 372.1666; found:
372.1665.
The deprotection of ribo compounds 27–31 has been reported earli-
er.10
(D)-1′,2′-cis-(3′,6′-O-Benzyl)-carba-dT (1-{(1S,2R,3S)-3-(Benzy-
loxy)-2-[(benzyloxy)methyl]cyclopentyl}-5-methylpyrimidine-
2,4(1H,3H)-dione) (33a) and (D)-1′,2′-cis-(3′,6′-O-Benzyl)-carba-O2-
dT [2-({(1S,2R,3S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]cyclopen-
tyl}oxy)-5-methylpyrimidin-4(3H)-one] (33b)
Rf = 0.58 (CH2Cl2/MeOH, 85:15); [α]D28 –65 (c 0.1, MeOH).
The IR and NMR analytical data are identical to those reported earli-
er.10
HRMS (ESI+): m/z [M + H]+ calcd for C17H21N2O5: 333.1445; found:
333.1453.
The reaction was carried out according to the general coupling proce-
dure with cyclopentanol (1S,2R)-32 (500 mg, 1.60 mmol), PPh3 (629
mg, 2.40 mmol), N3-benzoylthymine (553 mg, 2.40 mmol) and DIAD
(475 μL, 2.40 mmol) in MeCN (25 mL). Purification on silica gel (pe-
troleum ether/EtOAc, 1:2, petroleum ether/EtOAc, 1:2 + 10% Et3N,
CH2Cl2/MeOH, 98:2 to 95:5) afforded 33a and 33b.
(D)-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) (24)
The reaction was carried out according to the general dihydroxylation
procedure with 7a (75.0 mg, 252 μmol), AD-mix β (353 mg) and
methanesulfonamide (24.0 mg, 252 μmol) in t-BuOH/H2O (2:1, 5 mL).
Purification on RP18 silica gel by automated flash chromatography
(H2O/MeCN, 99:1 to 0:100) and freeze-drying (H2O/MeCN, 1:1) af-
forded 24 (81.1 mg, 97%) as a colorless cotton. The use of AD-mix α
led to an 83% yield
33a
Yield: 263 mg (39%); colorless resin; Rf = 0.63 (CH2Cl2/MeOH, 95:5);
[α]D25 –65 (c 0.1, MeOH).
IR (neat): 3173, 3030, 2860, 1663, 1453, 1271, 1089, 1066, 734 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.86 (br s, 1 H, NH), 7.40–7.26 (m, 8 H,
H-Bn), 7.21–7.15 (m, 2 H, H-Bn), 7.09–7.07 (m, 1 H, H-6), 4.95–4.85
(m, 1 H, H-1′), 4.58–4.48 (m, 2 H, CH2Ph), 4.32–4.24 (m, 2 H, CH2Ph),
4.23–4.16 (m, 1 H, H-3′), 3.47 (dd, 2J = 9.9 Hz, 3J = 4.9 Hz, 1 H, H-6a′),
3.34 (dd, 2J = 9.9 Hz, 3J = 3.1 Hz, 1 H, H-6b′), 2.66–2.58 (m, 1 H, H-2′),
2.38–2.29 (m, 1 H, H-4a′), 2.11–1.96 (m, 2 H, H-5′), 1.75 (d, 4J = 1.1 Hz,
3 H, CH3), 1.74–1.64 (m, 1 H, H-4b′).
Rf = 0.29 (CH2Cl2/MeOH, 85:15); [α]D25 –92 (c 0.1, MeOH).
The IR and NMR analytical data are identical to those reported earli-
er.10
HRMS (ESI+): m/z [M + H]+ calcd for C17H22N3O4: 332.1605; found:
332.1609.
(D)-1′,2′-cis-(6′-O-Benzyl)-carba-ribo-adenosine (9-{(1S,2R,3R,4S)-
2-[(Benzyloxy)methyl]-3,4-dihydroxycyclopentyl}-9H-purin-6-
amine) (25)
13C NMR (101 MHz, CDCl3): δ = 164.0 (Cq-4), 151.6 (Cq-2), 139.4 (C-6),
138.5 (Cq-Bn), 137.8 (Cq-Bn), 128.5 (2 × C-Bn), 128.5 (2 × C-Bn), 127.9
(C-Bn), 127.8 (2 × C-Bn), 127.8 (C-Bn), 127.6 (2 × C-Bn), 108.9 (C-5),
81.0 (C-3′), 73.5 (CH2Ph), 71.6 (CH2Ph), 68.8 (C-6′), 58.0 (C-1′), 46.7 (C-
2′), 30.4 (C-4′), 27.8 (C-5′), 12.5 (CH3).
HRMS (ESI+): m/z [M + H]+ calcd for C25H29N2O4: 421.2122; found:
421.2128.
The reaction was carried out according to the general dihydroxylation
procedure with 11 (50 mg, 156 μmol), AD-mix β (218 mg) and meth-
anesulfonamide (14.8 mg, 156 μmol) in t-BuOH/H2O (2:1, 6 mL). Puri-
fication on RP18 silica gel (H2O/MeCN, 97:3 to 0:100) and freeze-dry-
ing (H2O/MeCN, 1:1) afforded 25 (53.7 mg, 97%) as a colorless cotton.
The use of AD-mix α led to a 96% yield.
33b
Rf = 0.53 (CH2Cl2/MeOH, 85:15); [α]D25 21 (c 0.1, MeOH).
Yield: 161 mg (24%); colorless resin; Rf = 0.60 (CH2Cl2/MeOH, 95:5).
The IR and NMR analytical data are identical to those reported earli-
er.10
HRMS (ESI+): m/z [M + H]+ calcd for C18H22N5O3: 356.1717; found:
IR (neat): 3029, 2859, 1654, 1573, 1295, 1093, 1043, 908, 728, 696
cm–1
.
1H NMR (400 MHz, CDCl3): δ = 10.6 (br s, 1 H, NH), 7.57–7.53 (m, 1 H,
H-6), 7.37–7.19 (m, 10 H, H-Bn), 5.61–5.55 (m, 1 H, H-1′), 4.61–4.37
(m, 4 H, 2 × CH2Ph), 3.99–3.92 (m, 1 H, H-3′), 3.68–3.58 (m, 2 H, H-6′),
2.61–2.51 (m, 1 H, H-2′), 2.27–2.04 (m, 2 H, H-5a′, H-4a′), 1.99–1.86
(m, 4 H, CH3, H-5b′), 1.81–1.71 (m, 1 H, H-4b′).
13C NMR (101 MHz, CDCl3): δ = 165.0 (Cq-4), 155.3 (Cq-2), 151.5 (C-6),
138.6 (Cq-Bn), 138.4 (Cq-Bn), 128.5 (2 × C-Bn), 128.4 (2 × C-Bn), 127.7
(2 × C-Bn), 127.7 (3 × C-Bn), 127.6 (C-Bn), 117.4 (C-5), 81.3 (C-3′), 79.6
(C-1′), 73.2 (CH2Ph), 71.6 (CH2Ph), 67.5 (C-6′), 50.4 (C-2′), 30.2 (C-5′),
29.1 (C-4′), 12.5 (CH3).
356.1731.
(D)-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) (26)
The reaction was carried out according to the general dihydroxylation
procedure with 10 (50.0 mg, 148 μmol), AD-mix β (207 mg) and
methanesulfonamide (14.1 mg, 148 μmol) in t-BuOH/H2O (1:1, 6 mL).
Purification on RP18 silica gel (H2O/MeCN, 97:3 to 0:100) and freeze-
drying (H2O/MeCN, 1:1) afforded 26 (52.2 mg, 95%) as a colorless cot-
ton. The use of AD-mix α led to a 95% yield.
HRMS (ESI+): m/z [M + H]+ calcd for C25H29N2O4: 421.2122; found:
421.2122.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

L
S. Weising et al.
Paper
Synthesis
(D)-1′,2′-cis-(3′,6′-O-Benzyl)-carba-dU (1-{(1S,2R,3S)-3-(Benzy-
loxy)-2-[(benzyloxy)methyl]cyclopentyl}pyrimidine-2,4(1H,3H)-
dione) (34a) and (D)-1′,2′-cis-(3′,6′-O-Benzyl)-carba-O2-dU [2-
({(1S,2R,3S)-3-(Benzyloxy)-2-[(benzyloxy)methyl]cyclopen-
tyl}oxy)pyrimidin-4(3H)-one] (34b)
Rf = 0.28 (CH2Cl2/MeOH, 95:5); [α]D25 –131 (c 0.1, MeOH).
IR (neat): 3340, 3087, 2948, 2861, 1617, 1480, 1363, 1281, 1068, 788,
695 cm–1
1H NMR (300 MHz, CDCl3): δ = 7.37–7.14 (m, 11 H, H-Bn, H-6), 5.61
(d, 3J = 7.4 Hz, 1 H, H-5), 5.02–4.90 (m, 1 H, H-1′), 4.50 (s, 2 H, CH2Ph),
4.25–4.17 (m, 3 H, CH2Ph, H-3′), 3.43 (dd, 2J = 9.8 Hz, 3J = 4.2 Hz, 1 H,
H-6a′), 3.26 (dd, 2J = 9.8 Hz, 3J = 3.5 Hz, 1 H, H-6b′), 2.76–2.66 (m, 1 H,
H-2′), 2.36–2.23 (m, 1 H, H-4a′), 2.04–1.89 (m, 2 H, H-5′), 1.75–1.60
(m, 1 H, H-4b′).
13C NMR (76 MHz, CDCl3): δ = 165.7 (Cq-4), 157.3 (Cq-2), 143.9 (C-6),
138.7 (Cq-Bn), 138.2 (Cq-Bn), 128.5 (4 × C-Bn), 127.73 (2 × C-Bn),
127.67 (3 × C-Bn), 127.6 (C-Bn), 93.2 (C-5), 81.2 (C-3′), 73.3 (CH2Ph),
71.3 (CH2Ph), 69.1 (C-6′), 58.7 (C-1′), 46.1 (C-2′), 30.4 (C-4′), 27.9 (C-
5′).
.
The reaction was carried out according to the general coupling proce-
dure with cyclopentanol (1S,2R)-32 (1.20 g, 3.84 mmol), PPh3 (1.51 g,
5.67 mmol), N3-benzoyluracil (1.25 g, 5.67 mmol) and DIAD (1.14 mL,
5.67 mmol) in MeCN (50 mL). Purification on silica gel with automat-
ed flash chromatography (petroleum ether/EtOAc, 2:1 to 1:2, petro-
leum ether/acetone, 2:1 to 1:3, petroleum ether/EtOAc, 1:2 + 10% Et3N
to 100% EtOAc) afforded 34a and 34b.
34a
Yield: 484 mg (31%); colorless resin; Rf = 0.59 (CH2Cl2/MeOH, 95:5);
[α]D25 –135 (c 0.1, MeOH).
IR (neat): 3170, 3030, 2951, 2862, 1671, 1454, 1270, 1027, 733 cm–1
HRMS (ESI+): m/z [M + H]+ calcd for C24H28N3O3: 406.2125; found:
406.2127.
.
1H NMR (300 MHz, CDCl3): δ = 9.12 (br s, 1 H, NH), 7.41–7.14 (m, 11
H, H-Bn, H-6), 5.57–5.50 (m, 1 H, H-5), 4.99–4.87 (m, 1 H, H-1′), 4.57–
4.46 (m, 2 H, CH2Ph), 4.32–4.27 (m, 2 H, CH2Ph), 4.21–4.12 (m, 1 H, H-
3′), 3.46 (dd, J = 9.9 Hz, J = 4.7 Hz, 1 H, H-6a′), 3.33 (dd, J = 9.9 Hz,
3J = 3.1 Hz, 1 H, H-6b′), 2.67–2.57 (m, 1 H, H-2′), 2.39–2.26 (m, 1 H, H-
4a′), 2.14–1.90 (m, 2 H, H-5′), 1.77–1.61 (m, 1 H, H-4b′).
13C NMR (76 MHz CDCl3): δ = 163.6 (Cq-4), 151.6 (Cq-2), 143.2 (C-6),
138.5 (Cq-Bn), 137.6 (Cq-Bn), 128.6 (2 × C-Bn), 128.5 (2 × C-Bn), 128.0
(C-Bn), 127.9 (2 × C-Bn), 127.8 (3 × C-Bn), 100.7 (C-5), 80.9 (C-3′), 73.6
(CH2Ph), 71.5 (CH2Ph), 68.6 (C-6′), 58.1 (C-1′), 46.6 (C-2′), 30.3 (C-4′),
27.8 (C-5′).
(D)-1′,2′-cis-(3′,6′-O-Benzyl)-carba-O2-dC [2-({(1S,2R,3S)-3-(Benzy-
loxy)-2-[(benzyloxy)methyl]cyclopentyl}oxy)pyrimidin-4-amine]
(35b)
2
3
2
The reaction was carried out according to the general coupling proce-
dure with cyclopentanol (1S,2R)-32 (146 mg, 467 μmol), PPh3 (184
mg, 701 μmol), N4-acetylcytosine (107 g, 701 μmol) and DIAD (128
μL, 701 μmol) in THF (7.5 mL). Purification on silica gel with automat-
ed flash chromatography (CH2Cl2/MeOH, 98:2 to 85:15) afforded 35b
(127 mg, 67%) as a colorless resin.
Rf = 0.50 (CH2Cl2/MeOH, 95:5).
IR (neat): 3331, 3176, 3029, 2934, 2861, 1627, 1588, 1403, 1292,
HRMS (ESI+): m/z [M + H]+ calcd for C24H27N2O4: 407.1965; found:
407.1967.
1091, 734, 695 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.99 (d, 3J = 5.7 Hz, 1 H, H-6), 7.37–7.17
(m, 10 H, H-Bn), 6.02 (d, 3J = 5.7 Hz, 1 H, H-5), 5.66–5.60 (m, 1 H, H-1′),
4.87 (br s, 2 H, NH2), 4.60–4.43 (m, 4 H, 2 × CH2Ph), 4.08–4.01 (m, 1 H,
H-3′), 3.75 (dd, 2J = 9.4 Hz, 3J = 8.2 Hz, 1 H, H-6a′), 3.64 (dd, 2J = 9.4 Hz,
3J = 6.5 Hz, 1 H, H-6b′), 2.60–2.51 (m, 1 H, H-2′), 2.24–2.10 (m, 2 H, H-
5a′, H-4a′), 1.94–1.67 (m, 2 H, H-5b′, H-4b′).
34b
Yield: 264 mg (17%); colorless resin; Rf = 0.53 (CH2Cl2/MeOH, 95:5).
IR (neat): 3063, 3029, 2861, 1664, 1591, 1554, 1092, 1061, 908, 830,
695 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 11.1 (br s, 1 H, NH), 7.74 (d, 3J = 6.6 Hz,
1 H, H-6), 7.42–7.19 (m, 10 H, H-Bn), 6.07 (d, 3J = 6.6 Hz, 1 H, H-5),
5.71–5.62 (m, 1 H, H-1′), 4.62–4.41 (m, 4 H, 2 × CH2Ph), 4.05–3.95 (m,
1 H, H-3′), 3.70–3.62 (m, 2 H, H-6′), 2.65–2.53 (m, 1 H, H-2′), 2.31–
2.06 (m, 2 H, H-5a′, H-4a′), 2.00–1.71 (m, 2 H, H-5b′, H-4b′).
13C NMR (101 MHz, CDCl3): δ = 165.0 (Cq-4), 164.7 (Cq-2), 157.7 (C-6),
138.9 (Cq-Bn), 138.8 (Cq-Bn), 128.4 (2 × C-Bn), 128.3 (2 × C-Bn), 127.8
(2 × C-Bn), 127.6 (2 × C-Bn), 127.5 (C-Bn), 127.4 (C-Bn), 99.2 (C-5),
81.9 (C-3′), 77.6 (C-1′), 73.1 (CH2Ph), 71.6 (CH2Ph), 68.2 (C-6′), 50.6 (C-
2′), 30.3 (C-5′), 29.1 (C-4′).
13C NMR (76 MHz, CDCl3): δ = 165.0 (Cq-4), 157.1 (Cq-2), 155.2 (C-6),
128.6 (Cq-Bn), 138.4 (Cq-Bn), 128.5 (2 × C-Bn), 128.4 (2 × C-Bn),
127.78 (2 × C-Bn), 127.75 (2 × C-Bn), 127.71 (C-Bn), 127.66 (C-Bn),
108.9 (C-5), 81.3 (C-3′), 80.2 (C-1′), 73.2 (CH2Ph), 71.6 (CH2Ph), 67.5
(C-6′), 50.4 (C-2′), 30.2 (C-5′), 29.1 (C-4′).
HRMS (ESI+): m/z [M + H]+ calcd for C24H28N3O3: 406.2125; found:
406.2130.
(D)-1′,2′-cis-(3′,6′-O-Benzyl)-carba-6-chloro-dA (9-{(1S,2R,3S)-3-
(Benzyloxy)-2-[(benzyloxy)methyl]cyclopentyl}-6-chloro-9H-pu-
rine) (36)
HRMS (ESI+): m/z [M + H]+ calcd for C24H27N2O4: 407.1965; found:
407.1969.
The reaction was carried out according to the general coupling proce-
dure with cyclopentanol (1S,2R)-32 (157 mg, 503 μmol), PPh3 (198
mg, 755 μmol), 6-chloropurine (117 mg, 755 μmol) and DIAD (150 μL,
755 μmol) in THF (10 mL). Purification on silica gel with automated
flash chromatography (petroleum ether/EtOAc, 3:1 to 1:4) afforded
36 (176 mg, 78%) as a colorless resin.
(D)-1′,2′-cis-(3′,6′-O-Benzyl)-carba-dC (4-Amino-1-{(1S,2R,3S)-3-
(Benzyloxy)-2-[(benzyloxy)methyl]cyclopentyl}pyrimidin-2(1H)-
one) (35a)
The reaction was carried out according to the procedure for the syn-
thesis of 7a with uridine derivative 34a (276 mg, 680 μmol), 1,2,4-tri-
azole (423 mg, 6.12 mmol), POCl3 (123 μL, 1.31 mmol) and Et3N (0.81
mL, 5.9 mmol) in MeCN (5 + 5 mL). Amination was performed with
25% aqueous NH4OH solution (15 mL). Purification on RP18 silica gel
with automated flash chromatography (H2O/MeCN, 99:1 to 0:100)
and on silica gel (CH2Cl2/MeOH, 95:5 to 85:15) afforded 35a (212 mg,
77%) as a colorless foam.
Rf = 0.55 (petroleum ether/EtOAc, 1:2); [α]D25 –7 (c 0.1, MeOH).
IR (neat): 3062, 3030, 2861, 1590, 1557, 1338, 1208, 1095, 737 cm–1
.
1H NMR (600 MHz, CDCl3): δ = 8.69 (s, 1 H, H-2), 8.30 (s, 1 H, H-8),
7.39–7.22 (m, 8 H, H-Bn), 7.04–6.98 (m, 2 H, H-Bn), 5.32–5.26 (m, 1 H,
H-1′), 4.59 (d, 2J = 11.7 Hz, 1 H, CHHPh), 4.53 (d, 2J = 11.7 Hz, 1 H, CH-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

M
S. Weising et al.
Paper
Synthesis
HPh), 4.27–4.22 (m, 1 H, H-3′), 4.12 (d, 2J = 11.5 Hz, 1 H, CHHPh), 4.04
(d, 2J = 11.5 Hz, 1 H, CHHPh), 3.19–3.15 (m, 2 H, H-6′), 2.80–2.74 (m, 1
H, H-2′), 2.52–2.39 (m, 3 H, H-5′, H-4a′), 1.89–1.81 (m, 1 H, H-4b′).
HRMS (ESI+): m/z [M + H]+ calcd for C25H27ClN5O2: 464.1848; found:
464.1860.
13C NMR (151 MHz, CDCl3): δ = 152.2 (Cq-6), 151.9 (C-2), 150.8 (Cq-4),
145.4 (C-8), 138.3 (Cq-Bn), 137.2 (Cq-Bn), 131.0 (Cq-5), 128.6 (2 × C-
Bn), 128.2 (2 × C-Bn), 128.0 (C-Bn), 127.9 (C-Bn), 127.8 (4 × C-Bn),
81.0 (C-3′), 73.5 (CH2Ph), 71.8 (CH2Ph), 68.2 (C-6′), 56.6 (C-1′), 48.6 (C-
2′), 30.4 (C-4′), 28.8 (C-5′).
HRMS (ESI+): m/z [M + H]+ calcd for C25H26ClN4O2: 449.1739; found:
449.1745.
(D)-1′,2′-cis-(3′,6′-O-Benzyl)-carba-dG (2-Amino-9-{(1S,2R,3S)-3-
(benzyloxy)-2-[(benzyloxy)methyl]cyclopentyl}-1,9-dihydro-6H-
purin-6-one) (38)
A mixture of 37 (148 mg, 319 μmol) and 0.5 M aqueous NaOH (10 mL)
was heated at reflux overnight. After neutralization with AcOH, the
solvent was evaporated. Purification on RP18 silica gel with automated
flash chromatography (H2O/MeCN, 99:1 to 0:100) afforded 38 (131
mg, 92%) as a colorless cotton.
Rf = 0.26 (CH2Cl2/MeOH, 95:5); [α]D25 –38 (c 0.1, MeOH).
(D)-1′,2′-cis-(3′,6′-O-Benzyl)-carba-dA (9-{(1S,2R,3S)-3-(Benzy-
loxy)-2-[(benzyloxy)methyl]cyclopentyl}-9H-purin-6-amine) (39)
IR (neat): 3449, 3364, 2873, 2850, 1680, 1619, 1481, 1357, 1089,
The 6-chloropurine 36 (27.1 mg, 60.6 μmol) was dissolved in 7 M NH3
in MeOH (1.5 mL) and heated to 80 °C (microwave 100 W) for 2 h. Pu-
rification on silica gel (CH2Cl2/MeOH, 9:1) afforded 39 (25.5 mg, 98%)
as a colorless foam.
1072, 749, 697 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 10.5 (br s, 1 H, NH), 7.68 (s, 1 H, H-
8), 7.38–7.18 (m, 8 H, H-Bn), 7.13–7.06 (m, 2 H, H-Bn), 6.40 (br s, 2 H,
NH2), 4.94–4.85 (m, 1 H, H-1′), 4.55–4.44 (m, 2 H, CH2Ph), 4.22–4.07
(m, 3 H, CH2Ph, H-3′), 3.21 (dd, 2J = 9.7 Hz, 3J = 5.9 Hz, 1 H, H-6a′), 3.09
(dd, 2J = 9.7 Hz, 3J = 6.6 Hz, 1 H, H-6b′), 2.61–2.53 (m, 1 H, H-2′), 2.34–
2.14 (m, 3 H, H-4a′, H-5′), 1.74–1.63 (m, 1 H, H-4b′).
Rf = 0.43 (CH2Cl2/MeOH, 95:5); [α]D25 –18 (c 0.1, MeOH).
IR (neat): 3113, 2910, 2858, 1682, 1604, 1299, 1096, 1073, 757, 703,
662 cm–1
.
13C NMR (101 MHz, DMSO-d6): δ = 156.8 (Cq-6), 153.3 (Cq-2), 151.5
(Cq-4), 138.6 (Cq-Bn), 138.0 (Cq-Bn), 136.3 (C-8), 128.2 (2 × C-Bn),
128.0 (2 × C-Bn), 127.5 (2 × C-Bn), 127.3 (C-Bn), 127.22 (C-Bn), 127.19
(2 × C-Bn), 116.5 (Cq-5), 81.0 (C-3′), 72.1 (CH2Ph), 70.2 (CH2Ph), 67.8
(C-6′), 54.0 (C-1′), 47.5 (C-2′), 29.4 (C-4′), 28.0 (C-5′).
HRMS (ESI+): m/z [M + H]+ calcd for C25H28N5O3: 446.2187; found:
446.2202.
1H NMR (600 MHz, CDCl3): δ = 8.24 (s, 1 H, H-2), 7.77 (s, 1 H, H-8),
7.30–7.15 (m, 8 H, H-Bn), 7.04–6.98 (m, 2 H, H-Bn), 6.13 (br s, 2 H,
NH2), 5.17–5.09 (m, 1 H, H-1′), 4.51 (d, 2J = 11.7 Hz, 1 H, CHHPh), 4.46
(d, 2J = 11.7 Hz, 1 H, CHHPh), 4.22–4.18 (m, 1 H, H-3′), 4.07 (d, 2J = 11.6
Hz, 1 H, CHHPh), 4.01 (d, 2J = 11.6 Hz, 1 H, CHHPh), 3.12–3.09 (m, 2 H,
H-6′), 2.71–2.65 (m, 1 H, H-2′), 2.41–2.26 (m, 3 H, H-4a′, H-5), 1.79–
1.71 (m, 1 H, H-4b′).
13C NMR (151 MHz, CDCl3): δ = 155.0 (Cq-6), 151.7 (C-2), 150.5 (Cq-4),
141.0 (C-8), 138.5 (Cq-Bn), 137.7 (Cq-Bn), 128.5 (2 × C-Bn), 128.4 (2 x
C-Bn), 127.81 (C-Bn), 127.79 (2 × C-Bn), 127.77 (C-Bn), 127.7 (2 × C-
Bn), 119.6 (Cq-5), 81.2 (C-3′), 73.4 (CH2Ph), 71.6 (CH2Ph), 68.4 (C-6′),
55.8 (C-1′), 48.5 (C-2′), 30.5 (C-4′), 29.0 (C-5′).
HRMS (ESI+): m/z [M + H]+ calcd for C25H28N5O2: 430.2238; found:
430.2248.
(D)-1′,2′-cis-carba-dT (1-[(1S,2R,3S)-3-Hydroxy-2-(hydroxymeth-
yl)cyclopentyl]-5-methylpyrimidine-2,4(1H,3H)-dione) (40)
The reaction was carried out according to the general debenzylation
procedure above with 33a (150 mg, 357 μmol) and Pd/C (10%) in
MeOH (12 mL). Purification on RP18 silica gel with automated flash
chromatography (H2O/MeCN, 99:1 to 0:100) afforded 40 (79.8 g, 93%)
as a colorless cotton.
Rf = 0.53 (CH2Cl2/MeOH, 80:20); [α]D25 –87 (c 0.1, MeOH).
(D)-1′,2′-cis-(3′,6′-O-Benzyl)-carba-6-chloro-dG (9-{(1S,2R,3S)-3-
(Benzyloxy)-2-[(benzyloxy)methyl]cyclopentyl}-6-chloro-9H-pu-
rin-2-amine) (37)
IR (neat): 3351, 3026, 2955, 2822, 1651, 1471, 1400, 1270, 1044, 760
cm–1
.
The reaction was carried out according to the general coupling proce-
dure with cyclopentanol (1S,2R)-32 (238 mg, 762 μmol), PPh3 (299
mg, 1.14 mmol), 2-amino-6-chloropurine (193 mg, 1.14 mmol) and
DIAD (226 μL, 1.14 mmol) in THF (15 mL). Purification on silica gel
with automated flash chromatography (petroleum ether/EtOAc, 3:1
to 1:4) afforded 37 (237 mg, 67%) as a colorless resin.
1H NMR (300 MHz, D2O): δ = 7.51 (q, 4J = 1.2 Hz, 1 H, H-6), 5.08–4.94
(m, 1 H, H-1′), 4.26–4.15 (m, 1 H, H-3′), 3.59 (dd, 2J = 11.6 Hz, 3J = 5.6
Hz, 1 H, H-6a′), 3.48 (dd, 2J = 11.6 Hz, 3J = 7.7 Hz, 1 H, H-6b′), 2.41–2.17
(m, 3 H, H-2′, H-4a′, H-5a′), 2.12–1.95 (m, 1 H, H-5b′), 1.91 (d, 4J = 1.2
Hz, 3 H, CH3), 1.73–1.56 (m, 1 H, H-4b′).
13C NMR (76 MHz, D2O): δ = 166.7 (Cq-4), 152.8 (Cq-2), 140.8 (C-6),
110.0 (C-5), 73.6 (C-3′), 59.3 (C-6′), 57.3 (C-1′), 50.1 (C-2′), 31.5 (C-4′),
26.4 (C-5′), 11.4 (CH3).
Rf = 0.48 (petroleum ether/EtOAc, 1:2); [α]D25 –52 (c 0.1, MeOH).
IR (neat): 3316, 3199, 2942, 2860, 1606, 1558, 1454, 1370, 1090,
1064, 910, 733, 696 cm–1
.
HRMS (ESI+): m/z [M + H]+ calcd for C11H17N2O4: 241.1183; found:
1H NMR (400 MHz, CDCl3): δ = 7.88 (s, 1 H, H-8), 7.39–7.19 (m, 8 H, H-
Bn), 7.12–7.05 (m, 2 H, H-Bn), 5.11 (br s, 2 H, NH2), 5.10–5.02 (m, 1 H,
H-1′), 4.57 (d, 2J = 11.9 Hz, 1 H, CHHPh), 4.51 (d, 2J = 11.9 Hz, 1 H, CH-
HPh), 4.23–4.14 (m, 2 H, H-3′, CHHPh), 4.09 (d, 2J = 11.5 Hz, 1 H, CH-
HPh), 3.21–3.16 (m, 2 H, H-6′), 2.74–2.64 (m, 1 H, H-2′), 2.45–2.22 (m,
3 H, H-4a′, H-5′), 1.86–1.74 (m, 1 H, H-4b′).
13C NMR (101 MHz, CDCl3): δ = 158.8 (Cq-6), 154.1 (Cq-4), 150.9 (Cq-2),
142.4 (C-8), 138.4 (Cq-Bn), 137.5 (Cq-Bn), 128.6 (2 × C-Bn), 128.5
(2 × C-Bn), 127.90 (C-Bn), 127.86 (C-Bn), 127.83 (2 × C-Bn), 127.80
(2 × C-Bn), 124.7 (Cq-5), 81.1 (C-3′), 73.5 (CH2Ph), 71.6 (CH2Ph), 68.3
(C-6′), 55.8 (C-1′), 48.3 (C-2′), 30.3 (C-4′), 28.8 (C-5′).
241.1187.
(D)-1′,2′-cis-carba-dU (1-[(1S,2R,3S)-3-Hydroxy-2-(hydroxymeth-
yl)cyclopentyl]pyrimidine-2,4(1H,3H)-dione) (41)
The uridine derivative 34a (70.3 mg, 173 μmol) was dissolved in
MeOH (10 mL) and cyclohexene (4 mL). Next, Pd(OH)2/C (20%) was
added and the reaction mixture was refluxed for 18 h. The mixture
was filtered and the solvent was removed under reduced pressure.
The crude product was purified on RP18 silica gel with automated
flash chromatography (H2O/MeCN, 99:1 to 0:100) and freeze-dried
(H2O) to yield 41 (30.1 mg, 77%) as a colorless cotton.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–O

N
S. Weising et al.
Paper
Synthesis
Rf = 0.40 (CH2Cl2/MeOH, 80:20); [α]D25 –140 (c 0.1, MeOH).
HRMS (ESI+): m/z [M + H]+ calcd for C11H16N5O2: 250.1299; found:
250.1307.
IR (neat): 3367, 2925, 2854, 1671, 1467, 1379, 1272, 1072, 1044, 811,
719 cm–1
.
(D)-1′,2′-cis-carba-dG (2-Amino-9-[(1S,2R,3S)-3-hydroxy-2-(hy-
droxymethyl)cyclopentyl]-1,9-dihydro-6H-purin-6-one) (44)
1H NMR (400 MHz, D2O): δ = 7.67 (d, 3J = 8.1 Hz, 1 H, H-6), 5.81 (d, 3J =
8.1 Hz, 1 H, H-5), 5.05–4.95 (m, 1 H, H-1′), 4.22–4.13 (m, 1 H, H-3′),
3.57 (dd, 2J = 11.7 Hz, 3J = 5.2 Hz, 1 H, H-6a′), 3.47 (dd, 2J = 11.7 Hz, 3J =
7.8 Hz, 1 H, H-6b′), 2.40–2.18 (m, 3 H, H-2′, H-4a′, H-5a′), 2.08–1.94
(m, 1 H, H-5b′), 1.70–1.57 (m, 1 H, H-4b′).
13C NMR (151 MHz, D2O): δ = 166.5 (Cq-4), 152.7 (Cq-2), 145.2 (C-6),
100.7 (C-5), 73.5 (C-3′), 59.2 (C-6′), 57.6 (C-1′), 49.9 (C-2′), 31.4 (C-4′),
26.4 (C-5′).
The reaction was carried out according to the general debenzylation
procedure above with 38 (62.5 mg, 140 μmol) and Pd/C (10%) in
MeOH/H2O (3:1, 15 mL). Purification on silica gel (CH2Cl2/MeOH, 8:2)
and freeze-drying (H2O) gave 44 (34.1 mg, 92%) as a colorless cotton.
Rf = 0.14 (CH2Cl2/MeOH, 80:20); [α]D25 –58 (c 0.1, MeOH).
IR (neat): 3317, 3114, 2947, 1687, 1602, 1533, 1364, 1177, 1076, 781,
694 cm–1
.
HRMS (ESI+): m/z [M + H]+ calcd for C10H15N2O4: 227.1026; found:
1H NMR (600 MHz, DMSO-d6): δ = 10.7 (br s, 1 H, NH), 7.66 (s, 1 H, H-
8), 6.51 (br s, 2 H, NH2), 4.91–4.84 (m, 1 H, H-1′), 4.76 (br s, 1 H, -OH),
227.1037.
2
4.37 (br s, 1 H, -OH), 4.15–4.10 (m, 1 H, H-3′), 3.21 (dd, J = 11.0 Hz,
(D)-1′,2′-cis-carba-dC (4-Amino-1-[(1S,2R,3S)-3-Hydroxy-2-(hy-
droxymethyl)cyclopentyl]pyrimidin-2(1H)-one) (42)
2
3
3J = 6.5 Hz, 1 H, H-6a′), 2.96 (dd, J = 11.0 Hz, J = 6.7 Hz, 1 H, H-6b′),
2.23–2.06 (m, 4 H, H-4a′, H-5′, H-2′), 1.56–1.49 (m, 1 H, H-4b′).
The cytidine derivative 35a (64.1 mg, 158 μmol) was dissolved in
MeOH (10 mL) and cyclohexene (4 mL). Next, Pd(OH)2/C (20%) was
added and the reaction mixture was refluxed for 18 h. The mixture
was filtered and the solvent was removed under reduced pressure.
The crude product was purified on RP18 silica gel with automated
flash chromatography (H2O/MeCN, 99:1 to 0:100) and freeze-dried
(H2O) to yield 42 (31.5 mg, 88%) as a colorless cotton.
13C NMR (151 MHz, DMSO-d6): δ = 156.9 (Cq-6), 153.4 (Cq-2), 151.4
(Cq-4), 136.7 (C-8), 116.4 (Cq-5), 72.6 (C-3′), 58.7 (C-6′), 54.1 (C-1′),
52.7 (C-2′), 32.1 (C-4′), 27.8 (C-5′).
HRMS (ESI+): m/z [M + H]+ calcd for C11H16N5O3: 266.1248; found:
266.1250.
Rf = 0.14 (CH2Cl2/MeOH, 80:20); [α]D25 –146 (c 0.1, MeOH).
IR (neat): 3285, 3152, 2929, 1632, 1494, 1292, 1048, 792, 459 cm–1
.
Funding Information
1H NMR (300 MHz, D2O): δ = 7.64 (d, 3J = 7.5 Hz, 1 H, H-6), 6.01 (d, 3J =
7.5 Hz, 1 H, H-5), 5.04–4.93 (m, 1 H, H-1′), 4.28–4.17 (m, 1 H, H-3′),
3.53–3.39 (m, 2 H, H-6′), 2.45–2.16 (m, 3 H, H-2′, H-4a′, H-5a′), 2.09–
1.93 (m, 1 H, H-5b′), 1.75–1.59 (m, 1 H, H-4b′).
13C NMR (76 MHz, D2O): δ = 165.8 (Cq-4), 158.7 (Cq-2), 144.6 (C-6),
95.1 (C-5), 73.6 (C-3′), 59.4 (C-6′), 58.3 (C-1′), 50.2 (C-2′), 31.4 (C-4′),
26.7 (C-5′).
The authors are grateful to Universität Hamburg for financial support.)(
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1609493.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
HRMS (ESI+): m/z [M + H]+ calcd for C10H16N3O3: 226.1186; found:
226.1192.
References
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