Synthesis of the sugar building block of bicyclo-RNA

Article abstract of DOI:10.1055/S-0029-1218650

We present the novel synthesis of two sugar units that are central intermediates for the formation of members of the bicyclo-DNA and -RNA family. The synthesis starts from commercially available 1,2:5,6-di-O-isopropylidene- α-D-glucofuranose. The key step involves the elaboration of a carbocyclic ring in a furanoside by rhodium(I)-catalyzed hydroacylation. Via this pathway, one of the sugar units is available in 8 steps and in an overall yield of 27%, while its deoxy derivative is obtained in 11 steps, which is 5 steps fewer than in our previous synthesis of this compound. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/S-0029-1218650

PAPER
823
Synthesis of the Sugar Building Block of Bicyclo-RNA
Synthesis of the
S
u
r
gar Buil
b
ding Block o
e
f
B
icyclo-R
n
N
A
I. Haziri, Peter Silhar, Dorte Renneberg, Christian J. Leumann*
Department of Chemistry and Biochemistry, University of Bern, Freiestr. 3, 3012 Bern, Switzerland
Fax +41(31)6313422; E-mail: leumann@ioc.unibe.ch
Received 17 September 2009; revised 2 November 2009
An important prerequisite for the extensive biological
testing of oligonucleotide analogues is convenient, high-
yielding access to the corresponding nucleosides and
building blocks for solid-phase oligonucleotide synthesis.
Abstract: We present the novel synthesis of two sugar units that are
central intermediates for the formation of members of the bicyclo-
DNA and -RNA family. The synthesis starts from commercially
available 1,2:5,6-di-O-isopropylidene-a-D-glucofuranose. The key
step involves the elaboration of a carbocyclic ring in a furanoside by Our current synthesis of the nucleosides of bc- and tc-
rhodium(I)-catalyzed hydroacylation. Via this pathway, one of the
sugar units is available in 8 steps and in an overall yield of 27%,
DNA is based on the central sugar intermediate 1
(Scheme 1), which is available in six steps from bicyclic
while its deoxy derivative is obtained in 11 steps, which is 5 steps
compound 3 and in an overall yield of 33%.2a Compound
fewer than in our previous synthesis of this compound.
3 in turn is available from D-mannose in 10 steps and in an
overall yield of 23% on a one-mole scale.4 Thus, a total of
Key words: glycosides, fused-ring systems, DNA, rhodium, catal-
ysis
16 steps are required to obtain compound 1 from D-man-
nose in an overall yield of 8%.
We recently became interested in the synthesis and bio-
The recent finding that genetically encoded microRNAs
logical properties of members of the bicyclo-RNA (bc-
(miRNAs) or small interfering RNAs (siRNAs) function
RNA) series. To study this series, convenient, high-
as regulators for protein translation has raised their profile
yielding access to the corresponding hydroxylated sugar
intermediate 2 is necessary. In previous work, Ravn and
Nielsen synthesized an unsaturated derivative of com-
in pharmaceutical research and has boosted the search for
chemically modified oligonucleotide analogues as inhibi-
tors and potential therapeutic agents.1 In the context of oli-
pound 2 from olefin 4 via a ring-closing-metathesis strat-
gonucleotide therapeutics, during the 1990s, our group
egy.5 We felt that a more direct approach to form the
developed the molecular platform of bicyclo-DNA (bc-
cyclopentane ring via intramolecular, rhodium(I)-cata-
DNA) (Scheme 1).2 One member of this family, tricyclo-
lyzed hydroacylation of intermediate 4 might be shorter
DNA (tc-DNA) shows high affinity and selectivity in
binding to complementary RNA, is highly resistant to-
and superior to existing methods. This approach would
not only permit easy access to hydroxylated sugar 2 to be
used for the synthesis of bc-RNA or tricyclo-RNA (tc-
RNA), but could also lead to the shorter and improved
synthesis of deoxy derivative 1. Here, we report on the
successful realization of this synthetic strategy.
wards biodegradation, and is functionally active as an an-
tisense agent.3
O
O
H
O
H
O
O
O
Our synthesis started with the already known benzyl-pro-
tected aldehyde 4 (Scheme 2), which is readily available
from commercial 1,2;5,6-di-O-isopropylidene-a-D-gluco-
furanose in four steps according to published
procedures5,6 and in an overall yield of 65%. With com-
pound 4 in hand, we investigated the rhodium(I)-cata-
lyzed hydroacylation reaction to give tricyclic compound
5. Initial experiments using Wilkinson’s catalyst [10
mol% (Ph3P)3RhCl] according to a known procedure7 un-
fortunately gave, in our hands, desired compound 5 in
only 5–24% yield. We, therefore, started to optimize the
catalyst system by changing the rhodium(I) source and
varying the phosphine ligands.8
base
base
OH
O
tricyclo-DNA
bicyclo-DNA
OMe
O
O
HO
1 R = H
O
R
O
O
O
2 R = OH
O
OBn
3
4
D-mannose
D-glucose
Fairlie and Bosnich reported that cationic rhodium cata-
lysts are typically more active and provide fewer side
products compared with neutral rhodium derivatives.8a
Such catalysts are readily prepared in situ from a rhodium
chloride precursor by substitution with silver(I) tetrafluo-
roborate (AgBF4) or silver(I) perchlorate. We, therefore,
investigated complexes prepared in situ from
Scheme 1 Retrosynthetic relations between the bicyclo-DNA mole-
cular platform, the common sugar precursor 1, and common hexoses
SYNTHESIS 2010, No. 5, pp 0823–0827
x
x
.
x
x
.2
0
1
0
Advanced online publication: 25.01.2010
DOI: 10.1055/s-0029-1218650; Art ID: T18209SS
© Georg Thieme Verlag Stuttgart · New York

824
A. I. Haziri et al.
PAPER
HO
O
O
1.7%
H
H
H
O
O
O
0.6%
4%
a
b
O
O
O
88%
98%
H
H
HO
HO
H
BnO
O
BnO
BnO
O
H
O
O
O
H
5
O
H
5
5.8%
4
5
6
H
5.8%
O
BnO
H
O
O
BnO
HO
HO
6
C-5 epimer of 6
H
H
O
O
Figure 1 1H NMR-NOE spectroscopic results relevant for the
assignment of the configuration at C-5 in compound 6 and for its C-5
epimer
d
c
OMe
OMe
79%
62%
BnO
OH
OH
OH
7
2
(α/β = 1:1)
The synthesis of compound 2 was then completed by the
Scheme 2 Reagents and conditions: (a) [Rh(nbd)2]BF4 (10 mol%), conversion of tricyclic compound 6 into methyl glycoside
7,9 which was obtained in a 1:1 anomeric ratio and in 79%
yield, followed by hydrogenolytic cleavage of the benzyl
group yielding target compound 2 in 62% yield. For the
1,2-bis(diphenylphosphino)benzene (12 mol%), DCE, 75 °C, 20 h;
(b) NaBH4 (2 equiv), MeOH, 0 °C, 1 h; (c) TsOH, MeOH, r.t., 24 h;
(d) H2, Pd(OH)2/C, MeOH, r.t., 16 h.
purpose of synthesizing bc-RNA nucleosides, there is no
need for the separation of the anomers of compound 2 as
the mixture can be used directly.
[Rh(cod)Cl]2 (cod = cycloocta-1,5-diene), AgBF4, and
nine different bis-phosphine ligands. The most active
complex in converting aldehyde 4 into cyclopentanone 5
turned out to be that containing 1,2-bis(diphenylphosphi-
no)benzene as a ligand. However, the cyclization reaction
was very slow and the maximum yield of product 5 was
only 45%. A dramatic improvement came by changing the
rhodium(I) source to [Rh(nbd)2]BF4 (nbd = norborna-
diene). After activation with hydrogen and using the bis-
phosphine ligand described above, ketone 5 was obtained
in reproducible yields of 78–98% with 10 mol% catalyst
loading. We attribute the higher activity to the better leav-
ing properties of norbornadiene compared with those of
cycloocta-1,5-diene upon catalyst activation.
To explore whether the above would also provide a con-
venient entry into the bc-DNA sugar series, we converted
hydroacylation/reduction product 6 into bis-benzylated
intermediate 8 (96% yield), which was then transformed
into an approximately 1:1 anomeric mixture of methyl
glycoside 9 (62% yield) (Scheme 3). The b-anomer of this
product could be separated off in pure form by flash chro-
matography. For ease of spectroscopic analysis, we per-
formed the rest of the steps with the pure b-anomer of 9.
With the aim of removing the remaining hydroxy group
using Barton and McCombie chemistry, we transformed
methyl glycoside 9 into the corresponding thiocarbamate
10 (88% yield),10 which after radical reduction with tribu-
tylstannane gave deoxy sugar 11 in 44% yield. Consider-
able efforts to improve this reaction by changing the
nature of the thiocarbamate group and the reducing agent
unfortunately did not lead to a higher yield of product 11.
The reason for this is most likely due to steric constraints
around the reacting center. The removal of the benzyl
groups by catalytic hydrogenation finally led to bc-DNA
sugar building block 12a in 74% yield (Scheme 3).
Encouraged by these results, we continued the synthesis
of target compound 2 via the reduction of ketone 5 with
sodium borohydride which afforded alcohol 6 in a highly
selective manner and in 88% yield. Only 4% yield of the
C-5 epimeric compound could be isolated. The relative
configuration of the hydroxy group in product 6 could be
unambiguously assigned by 1H NMR-NOE spectroscopic
experiments (Figure 1).
HO
c
BnO
BnO
H
H
H
(β-anomer of 9
O
O
H
O
only)
a
b
62%
OMe
O
O
88%
96%
BnO
O
BnO
BnO
O
OH
6
8
9
BnO
BnO
HO
H
H
O
O
O
d
e
74%
OMe
OMe
OMe
44%
BnO
BnO
OH
O
S
10
11
1
N
N
Scheme 3 Reagents and conditions: (a) NaH (2 equiv), BnBr (2.5 equiv), DMF, r.t., 20 h; (b) TsOH, MeOH, r.t., 24 h; (c) 1,1¢-thiocarbonyl-
diimidazole (2 equiv), THF, reflux, 4 h; (d) AIBN (0.2 equiv), Bu3SnH (4 equiv), toluene, reflux, 2 h; (e) H2, Pd(OH)2/C, MeOH, r.t., 16 h.
Synthesis 2010, No. 5, 823–827 © Thieme Stuttgart · New York

PAPER
Synthesis of the Sugar Building Block of Bicyclo-RNA
825
mL) followed by neutralization with 4 M AcOH (27 mL), the mix-
ture was extracted with CH2Cl2 (3 × 150 mL). The combined organ-
ic layers were dried (MgSO4) and evaporated, and the residue was
purified by flash chromatography (hexane–EtOAc, 1:3) to give
product 6 as a white solid, together with its C-5 epimer (0.15 g, 4%)
as a clear oil. Yield: 3.44 g (88%); Rf = 0.44 (hexane–EtOAc, 1:3).
1H NMR (300 MHz, CDCl3): d = 1.41 (s, 3 H, CH3), 1.61 (s, 3 H,
CH3), 1.69–1.80 (m, 1 H, H-6b), 1.95–2.20 (m, 3 H, 2 H-7, H-6a),
4.15–4.30 (m, 1 H, H-5), 4.46–4.50 (m, 2 H, CH2Ph, H-4a), 4.55 (d,
J = 3.6 Hz, 1 H, H-7b), 4.65 (d, J = 10.7 Hz, 1 H, CH2Ph), 5.88 (d,
J = 3.6 Hz, 1 H, H-3a), 7.28–7.42 (m, 5 H, Ph).
13C NMR (75 MHz, CDCl3): d = 27.5, 27.6, 30.2, 31.4, 67.3, 73.4,
84.6, 87.1, 90.8, 107.1, 114.2, 127.8, 128.5, 138.4.
HRMS (ESI): m/z [M + Na]+ calcd for C17H22O5Na: 329.1364;
found: 329.1365.
In conclusion, we have presented a robust and efficient
synthesis of the central sugar unit 2, which can be used for
the formation of bc- and tc-RNA. Starting from commer-
cial 1,2;5,6-di-O-isopropylidene-a-D-glucofuranose, the
product is formed in eight steps and in an overall yield of
27%. In addition, along the same synthetic avenue, build-
ing block 1 for the synthesis of bc- or tc-DNA becomes
available in 11 steps. Under the assumption that the con-
version of dibenzyl derivative 9 into deoxy compound 1
(Scheme 3) in the a-anomeric series is of similar efficien-
cy, an overall yield of 10% would be obtained. This cor-
responds to an improvement over the current synthesis,
which takes 16 steps (from D-mannose) and gives the
product in an overall yield of 8%.
C-5 Epimer of 6
Rf = 0.55 (hexane–EtOAc, 1:3).
Thin-layer chromatography (TLC) was performed on silica gel
plates (SIL G-25 UV254, Machery-Nagel). Visualization was effect-
ed by dipping the TLC plates into a staining reagent [phosphomo-
lybdic acid (12.5 g), cerium(IV) sulfate (5 g), concd H2SO4 (40
mL), H2O (460 mL)]. Flash chromatography was performed on sil-
1H NMR (300 MHz, CDCl3): d = 1.40 (s, 3 H, CH3), 1.61 (s, 3 H,
CH3), 1.90–2.10 (m, 2 H, H-6b, H-7b), 2.15–2.42 (m, 2 H, H-6a, H-
7a), 4.21 (s, 1 H, H-5), 4.40 (s, 1 H, H-4a), 4.53–4.63 (m, 2 H,
CH2Ph, H-7b), 4.70 (d, J = 10.9 Hz, 1 H, CH2Ph), 5.80 (d, J = 3.0
Hz, 1 H, H-3a), 7.28–7.42 (m, 5 H, Ph).
13C NMR (75 MHz, CDCl3): d = 27.6, 27.7, 31.3, 33.6, 68.0, 76.4,
82.7, 90.7, 93.5, 106.7, 113.9, 127.6, 128.8, 138.7.
1
ica gel 60A (particle size 0.040–0.063 mm). H NMR spectra were
recorded on a Bruker AC-300, Bruker DRX-400, or Bruker DRX-
500 spectrometer; chemical shifts are reported in ppm relative to the
undeuterated residual solvent peak (calibrated to 7.26 ppm for
CDCl3 and 2.49 ppm for DMSO-d6). 13C NMR spectra were record-
ed at 75 MHz on a Bruker Avance 300 MHz spectrometer; chemical
shifts are reported in ppm relative to the solvent peak (calibrated to
77.16 ppm for CDCl3 and to 39.7 ppm for DMSO-d6). Difference 1H
NMR-NOE experiments were recorded at 400 MHz. High-resolu-
tion ESI mass spectra were recorded on an Applied Biosystems Sci-
ex QSTAR Pulsar instrument. All reactions were performed in
oven-dried glassware under an atmosphere of Ar. Solvents for reac-
tions were dried over alumina (THF and CH2Cl2) or purchased from
Fluka (DMF and MeOH). Solvents for extractions and flash chro-
matography were distilled before use.
HRMS (ESI): m/z [M + Na]+ calcd for C17H22O5Na: 329.1364;
found: 329.1365.
3a-Benzyloxy-2-methoxyhexahydrocyclopenta[b]furan-3,6-diol
(7)
Compound 6 (1.06 g, 3.26 mmol) was stirred with 3% TsOH in
MeOH (15 mL) at r.t. for 24 h. The mixture was neutralized with
sat. aq Na2CO3 (3 mL), concentrated, diluted with H2O (30 mL),
and extracted with CH2Cl2 (3 × 30 mL). The combined organic
phases were dried (MgSO4) and evaporated, and the residue was pu-
rified by flash chromatography (hexane–EtOAc, 1:3) to give prod-
uct 7 as a 1:1 mixture of anomers in the form of a clear oil. Yield:
0.72 g (79%).
7a-Benzyloxy-2,2-dimethylhexahydrocyclopenta[4,5]furo[2,3-
d][1,3]dioxol-5-one (5)
Complex [Rh(nbd)2]BF4 (0.49 g, 1.30 mmol, 10 mol%) and 1,2-
bis(diphenylphosphino)benzene (0.44 g, 1.5 mmol, 12 mol%) were
suspended in DCE (20 mL), and the mixture was stirred at r.t. under
an atmosphere of Ar for ca. 10 min. Then, H2 was bubbled through
the solution for 10 min, followed by flushing again with Ar for 20
min to remove H2. Compound 4 (4.00 g, 13 mmol) in DCE (30 mL)
was then added dropwise to the solution, and the mixture was stirred
for 20 h at 75 °C. Product 5 was isolated by flash chromatography
(CH2Cl2–2% acetone) as a yellow oil. Yield: 3.92 g (98%); Rf = 0.32
(CH2Cl2–acetone, 98:2).
1H NMR (300 MHz, CDCl3): d = 1.40 (s, 3 H, CH3), 1.61 (s, 3 H,
CH3), 1.69–1.81 (m, 1 H, H-7b), 2.50–2.57 (m, 3 H, 2 H-6, H-7a),
4.17 (s, 1 H, H-4a), 4.61–4.65 (m, 2 H, CH2Ph, H-7b), 4.75 (d, J =
10.9 Hz, 1 H, CH2Ph), 5.95 (d, J = 3.6 Hz, 1 H, H-3a), 7.29–7.42
(m, 5 H, Ph).
If needed, the anomers can be separated by flash chromatography
under these conditions. Samples of the pure anomers were used for
analytical characterization.
b-Anomer
Rf = 0.32 (hexane–EtOAc, 1:3).
1H NMR (300 MHz, CDCl3): d = 1.90–2.29 (m, 4 H, 2 H-4, 2 H-5),
2.32 (d, J = 6.5 Hz, 1 H, OH-6), 3.02 (d, J = 3.5 Hz, 1 H, OH-3),
3.44 (s, 3 H, OMe), 3.96 (dd, J = 0.9, 3.4 Hz, 1 H, H-3), 4.10–4.20
(m, 1 H, H-6), 4.36–4.46 (m, 2 H, CH2Ph, H-6a), 4.50–4.75 (m, 1
H, CH2Ph), 5.00 (d, J = 1.1 Hz, 1 H, H-2), 7.28–7.42 (m, 5 H, Ph).
1H NMR-NOE (400 MHz, CDCl3): 3.96 (H-3) → 5.03 (H-2,
2.06%); 4.18 (H-6) → 2.32 (OH-6, 1.12%), 3.05 (OH-3, 0.57%),
4.44 (H-6a, 4.98%), 5.00 (H-2, 0.26%); 4.43 (H-6a) → 2.32 (OH-6,
0.87%), 3.05 (OH-3, 1.21%), 4.17 (H-6, 3.03%), 5.00 (H-2, 0.28%);
5.00 (H-2) → 3.96 (H-3, 2.13%).
13C NMR (75 MHz, CDCl3): d = 26.9, 27.2, 27.4, 35.9, 67.6, 81.9,
83.6, 97.4, 107.9, 114.3, 127.6, 127.7, 128.8, 137.9, 209.9.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C17H20O5Na: 327.1208;
13C NMR (75 MHz, CDCl3): d = 29.1, 32.3, 56.5, 65.1, 67.4, 72.5,
79.8, 87.7, 91.3, 112.1, 127.9, 128.4, 129.0, 137.5.
found: 327.1218.
HRMS (ESI): m/z [M + Na]+ calcd for C15H20O5Na: 303.1208;
found: 303.1209.
7a-Benzyloxy-2,2-dimethylhexahydrocyclopenta[4,5]furo[2,3-
d][1,3]dioxol-5-ol (6)
Compound 5 (3.92 g, 12 mmol) was dissolved in MeOH (80 mL)
and treated at 0 °C with NaBH4 (0.97 g, 25 mmol); the resulting
mixture was stirred for 1 h at 0 °C. After dilution with H2O (100
a-Anomer
Rf = 0.23 (hexane–EtOAc, 1:3).
1H NMR (300 MHz, CDCl3): d = 1.50–2.15 (m, 4 H, 2 H-4, 2 H-5),
2.25 (d, J = 8.4 Hz, 1 H, OH-6), 3.04 (d, J = 11.1 Hz, 1 H, OH-3),
Synthesis 2010, No. 5, 823–827 © Thieme Stuttgart · New York

826
A. I. Haziri et al.
PAPER
3.45 (s, 3 H, OMe), 3.86 (dd, J = 4.3, 10.9 Hz, 1 H, H-3), 4.05–4.15
(m, 1 H, H-6), 4.38 (d, J = 5.6 Hz, 1 H, H-6a), 4.59 (d, J = 12.0 Hz,
1 H, CH2Ph), 4.75 (d, J = 12.0 Hz, 1 H, CH2Ph), 4.96 (d, J = 4.3 Hz,
1 H, H-2), 7.28–7.42 (m, 5 H, Ph).
1H NMR-NOE (400 MHz, CDCl3): 3.81 (H-3) → 2.25 (OH-6,
0.65%), 3.04 (OH-3, 0.79%), 4.38 (H-6a, 0.40%), 4.96 (H-2,
6.33%); 4.05 (H-6) → 2.18 (OH-6, 1.07%), 3.44 (OH-3, 0.74%),
4.34 (H-6a, 5.68%), 4.92 (H-2, 0.63%); 4.37 (H-6a) → 3.04 (OH-3,
0.52%), 4.05 (H-6, 5.11%), 4.91 (H-2, 0.91%); 4.96 (H-2) → 3.86
(H-3, 5.25%).
13C NMR (75 MHz, CDCl3): d = 29.5, 31.5, 55.3, 66.9, 72.0, 79.1,
84.0, 86.9, 103.7, 126.8, 127.4, 128.4, 138.8.
HRMS (ESI): m/z [M + Na]+ calcd for C15H20O5Na: 303.1208;
found: 303.1209.
and extracted with CH2Cl2 (3 × 30 mL). The combined organic
phases were dried (MgSO4) and evaporated, and the residue was pu-
rified by flash chromatography (hexane–EtOAc, 1:2) to give the
anomers of product 9 as colorless oils. Yield: 0.94 g (33%) (b-ano-
mer), 0.83 g (29%) (a-anomer).
b-Anomer
Rf = 0.68 (hexane–EtOAc, 1:2).
1H NMR (300 MHz, CDCl3): d = 2.04 (d, J = 4.3 Hz, 4 H, 2 H-4, 2
H-5), 2.97 (d, J = 3.7 Hz, 1 H, OH-3), 3.44 (s, 3 H, OMe), 3.85–3.95
(m, 1 H, H-6), 3.99 (d, J = 3.7 Hz, 1 H, H-3), 4.39 (d, J = 10.9 Hz,
1 H, CH2Ph), 4.47–4.60 (m, 3 H, CH2Ph, H-6a), 4.73 (d, J = 11.8
Hz, 1 H, CH2Ph), 5.02 (s, 1 H, H-2), 7.28–7.45 (m, 10 H, 2 Ph).
1H NMR-NOE (400 MHz, CDCl3): 3.02 (OH-3) → 3.44 (OMe,
0.29%), 3.99 (H-3, 4.09%), 4.52 (H-6a, 3.17%), 5.00 (H-2, 2.18%);
3.88 (H-6) → 4.52 (H-6a, 8.84%); 3.99 (H-3) → 5.00 (H-2, 4.46%);
5.00 (H-2) → 3.44 (OMe, 6.07%), 3.99 (H-3, 3.70%).
13C NMR (75 MHz, CDCl3): d = 28.4, 29.1, 55.4, 67.1, 71.6, 79.3,
79.4, 85.3, 91.3, 110.6, 127.7, 127.8, 127.9, 128.3, 128.5, 128.8,
137.3, 138.6.
HRMS (ESI): m/z [M + Na]+ calcd for C22H26O5Na: 393.1678;
found: 393.1673.
2-Methoxyhexahydrocyclopenta[b]furan-3,3a,6-triol (2)
Compound 7 (b-anomer) (0.36 g, 1.28 mmol) was dissolved in an-
hyd MeOH (5 mL), and Pd(OH)2/C (300 mg) was added to the so-
lution. The mixture was degassed with Ar for 10 min, followed by
flushing with H2 for 10 min. Then, the mixture was stirred for 16 h
at r.t. After filtration through Celite, the solvent was removed and
the residue was purified by flash chromatography (hexane–EtOAc,
1:5) to give compound 2 as a colorless oil. Yield: 0.15 g (62%);
Rf = 0.22 (hexane–EtOAc, 1:5).
1H NMR (300 MHz, CDCl3): d = 1.60–1.85 (m, 2 H, H-4b, H-5b),
1.90–2.15 (m, 2 H, H-4a, H-5a), 2.46 (d, J = 6.0 Hz, 1 H, OH-6),
3.00 (s, 1 H, OH-3a), 3.26 (s, 1 H, OH-3), 3.46 (s, 3 H, OMe), 3.78
(s, 1 H, H-3), 4.15–4.19 (m, 1 H, H-6), 4.21 (d, J = 6.0 Hz, 1 H, H-
6a), 4.94 (d, J = 3.0 Hz, 1 H, H-2).
a-Anomer
Rf = 0.58 (hexane–EtOAc, 1:2).
1H NMR (300 MHz, CDCl3): d = 1.85–2.15 (m, 4 H, 2 H-4, 2 H-5),
2.98 (d, J = 11.1 Hz, 1 H, OH-3), 3.47 (s, 3 H, OMe), 3.60–3.90 (m,
2 H, H-3, H-6), 4.43 (d, J = 4.3 Hz, 1 H, H-6a), 4.50–4.75 (m, 4 H,
2 CH2Ph), 5.00 (d, J = 4.3 Hz, 1 H, H-2), 7.30–7.45 (m, 10 H, 2 Ph).
1H NMR-NOE (400 MHz, CDCl3): 3.02 (OH-3) → 3.50 (OMe,
0.61%), 3.78 (H-6, 0.63%), 3.88 (H-3, 4.60%), 4.40 (H-6a, 1.01%),
5.00 (H-2, 1.40%); 3.78 (H-6) → 3.01 (OH-3, 0.34%), 3.50 (OMe,
3.14%), 4.40 (H-6a, 9.38%), 5.00 (H-2, 0.15%); 4.40 (H-6a) → 3.01
(OH-3, 0.73%), 3.50 (OMe, 2.63%), 3.78 (H-6, 7.23%), 5.00 (H-2,
0.28%); 5.00 (H-2) → 3.01 (OH-3, 1.36%), 3.50 (OMe, 6.33%),
3.88 (H-3, 8.08%), 4.41 (H-6a, 0.83%).
13C NMR (75 MHz, CDCl3): d = 32.2, 34.3, 56.6, 72.4, 80.4, 84.8,
89.1, 111.2.
HRMS (ESI): m/z [M + Na]+ calcd for C8H14O5Na: 213.0739;
found: 213.0735.
5,7a-Bis(benzyloxy)-2,2-dimethylhexahydrocyclopenta[4,5]fu-
ro[2,3-d][1,3]dioxole (8)
Sodium hydride (0.38 g, 16 mmol) was suspended in anhyd DMF
(20 mL) and the mixture was cooled to 0 °C. To the mixture was
added a solution of alcohol 6 (2.47 g, 8 mmol) in anhyd DMF (5
mL) dropwise over a period of 30 min. The mixture was stirred at
50 °C for 1 h, then cooled to 0 °C. Then, BnBr (2.37 mL, 0.02 mol)
was added dropwise and the mixture was stirred at r.t. for 20 h. Af-
ter, DMF was removed in vacuo, the residue was taken up in CH2Cl2
(50 mL), and the solution was extracted with sat. NaHCO3 (2 × 50
mL). The organic phase was dried (MgSO4) and evaporated, and the
residue was purified by flash chromatography (hexane–EtOAc, 1:2)
to yield compound 8 as a slightly yellow oil. Yield: 3.06 g (96%);
Rf = 0.71 (hexane–EtOAc, 1:2).
1H NMR (300 MHz, CDCl3): d = 1.39 (s, 3 H, CH3), 1.62 (s, 3 H,
CH3), 1.70–2.15 (m, 4 H, 2 H-6, 2 H-7), 4.04–4.10 (m, 1 H, H-5),
4.40–4.70 (m, 6 H, 2 CH2Ph, H-7b, H-4a), 5.93 (d, J = 3.7 Hz, 1 H,
H-3a), 7.28–7.45 (m, 10 H, 2 Ph).
13C NMR (75 MHz, CDCl3): d = 27.4, 27.5, 27.8, 29.7, 67.2, 72.1,
80.1, 83.9, 84.4, 90.8, 107.0, 113.6, 127.72, 127.77, 127.8, 128.0,
128.5, 138.46, 138.48.
13C NMR (75 MHz, CDCl3): d = 28.2, 29.7, 55.4, 67.0, 72.0, 78.5,
79.3, 82.7, 87.1, 103.5, 126.9, 127.6, 127.9, 128.1, 128.5, 128.6,
138.2, 139.0.
HRMS (ESI): m/z [M + Na]+ calcd for C22H26O5Na: 393.1678;
found: 393.1674.
O-[3a,6-Bis(benzyloxy)-2-methoxyhexahydrocyclopenta[b]fu-
ran-3-yl] Imidazole-1-carbothioate (10)
To a solution of the b-anomer of compound 9 (0.94 g, 2.5 mmol) in
THF (20 mL) was added 1,1¢-thionocarbonyldiimidazole (0.91 g,
5.0 mmol) and the mixture was stirred at reflux for 4 h. The solvent
was evaporated and the residue was purified by flash chromatogra-
phy (hexane–EtOAc, 1:2) to give compound 10 as a yellowish oil.
Yield: 1.08 g (88%); Rf = 0.60 (hexane–EtOAc, 1:2).
1H NMR (300 MHz, CDCl3): d = 2.04–2.10 (m, 3 H, 2 H-4, H-5a),
2.22–2.25 (m, 1 H, H-5b), 3.50 (s, 3 H, OMe), 3.95–4.20 (m, 2 H,
H-3, H-6), 4.48–4.73 (m, 4 H, 2 CH2Ph), 5.13 (s, 1 H, H-6a), 5.77
(s, 1 H, H-2), 7.00 (d, J = 0.9 Hz, 1 H, H-2imidazole), 7.10–7.45 (m, 10
H, 2 Ph), 7.57 (d, J = 3.2 Hz, 1 H, H-4imidazole), 8.28 (d, J = 3.2 Hz,
1 H, H-5imidazole).
HRMS (ESI): m/z [M + Na]+ calcd for C24H28O5Na: 419.1834;
found: 419.1828.
13C NMR (75 MHz, CDCl3): d = 14.1, 28.5, 30.4, 56.2, 68.0, 70.1,
72.2, 79.7, 87.1, 87.6, 90.0, 108.3, 118.3, 127.7, 128.0, 128.1,
128.3, 128.8, 128.9, 131.2, 131.4, 137.2, 137.5, 138.7, 183.2.
HRMS (ESI): m/z [M + H]+ calcd for C26H29N2O5S: 481.1797;
found: 481.1782.
3a,6-Bis(benzyloxy)-2-methoxyhexahydrocyclopenta[b]furan-
3-ol (9)
Compound 8 (3.06 g, 7 mmol) was stirred with 3% TsOH in MeOH
(20 mL) at r.t. for 24 h. The mixture was neutralized with sat. aq
Na2CO3 (3 mL), concentrated in vacuo, diluted with H2O (30 mL),
Synthesis 2010, No. 5, 823–827 © Thieme Stuttgart · New York

PAPER
Synthesis of the Sugar Building Block of Bicyclo-RNA
827
3a,6-Bis(benzyloxy)-2-methoxyhexahydrocyclopenta[b]furan
(11)
Acknowledgment
We gratefully thank the Swiss National Science Foundation (grant
no. 200020-115913) and the Association Monégasque contre les
Myopathies for financial support.
A solution of compound 10 (1.08 g, 2.2 mmol) in toluene (40 mL)
containing AIBN (65.6 mg, 0.4 mmol) was added dropwise within
1 h to a refluxing mixture of Bu3SnH (2.36 mL, 8.8 mmol) in tolu-
ene (80 mL). The mixture was stirred under reflux for 2 h. Evapo-
ration of the solvent and flash chromatography (hexane–EtOAc,
1:1) yielded product 11 as a yellowish oil. Yield: 0.35 g (44%); Rf =
0.81 (hexane–EtOAc, 1:1).
1H NMR (300 MHz, CDCl3): d = 1.90–2.30 (m, 5 H, H-3b, 2 H-4,
2 H-5), 2.54–2.63 (m, 1 H, H-3a), 3.40 (s, 3 H, OMe), 3.83–3.86 (m,
1 H, H-6), 4.40 (d, J = 8.4 Hz, 1 H, CH2Ph), 4.41–4.51 (m, 2 H, H-
6a, CH2Ph), 4.56 (d, J = 8.9 Hz, 1 H, CH2Ph), 4.74 (d, J = 8.9 Hz, 1
H, CH2Ph), 5.19 (dd, J = 1.6, 5.8 Hz, 1 H, H-2), 7.30–7.45 (m, 10
H, 2 Ph).
13C NMR (75 MHz, CDCl3): d = 28.9, 33.6, 46.1, 55.3, 67.1, 71.8,
72.2, 79.4, 86.8, 92.4, 106.5, 127.8, 128.0, 128.1, 128.3, 128.9,
138.8, 139.1.
HRMS (ESI): m/z [M + H]+ calcd for C22H26O4Na: 377.1723;
found: 377.1714.
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The analytical data were identical with those reported in the litera-
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Synthesis 2010, No. 5, 823–827 © Thieme Stuttgart · New York