Preparation of carbocyclic C-nucleosides from α-chlorooxime precursor

Article abstract of DOI:10.1002/ejoc.200900950

The syntheses of L-carbocyclic benzothiazolo, benzoxazolo, and benzimidazolo C-nor-nucleosides are described. The key step is the reaction of the C-chlorooxime 7, obtained by C-chlorination with N-chlorosuccinimide of [(1S,2R,3R,4R)-1tert-butyldimethylsil

Full text of DOI:10.1002/ejoc.200900950

FULL PAPER
DOI: 10.1002/ejoc.200900950
Preparation of Carbocyclic C-Nucleosides from α-Chlorooxime Precursor
Ugo Pradere,[a] Hiroki Kumamoto,[a] Vincent Roy,[a] and Luigi A. Agrofoglio*[a]
Keywords: Nucleosides / Heterocycles / Carbocycles / Fused-ring systems / Asymmetric synthesis
The syntheses of
L
-carbocyclic benzothiazolo, benzoxazolo,
pentane-4-carbohydroximic acid (6), with different α-amino
aromatic compounds. Acidic deprotection gave the benz-
oxazolo (11), benzimidazolo (12), and benzothiazolo (13) title
compounds, in good yields.
and benzimidazolo C-nor-nucleosides are described. The key
step is the reaction of the C-chlorooxime 7, obtained by C-
chlorination with N-chlorosuccinimide of [(1S,2R,3R,4R)-1-
tert-butyldimethylsiloxy-2,3-(O-isopropylidenedioxy)]cyclo-
Introduction
Nucleoside analogs[1] have received great attention be-
cause of their potent biological activities, and therefore,
much effort has been focused on their syntheses. One im-
portant class of modified nucleosides is the carbocyclic nu-
cleosides[2] in which the furanose ring is replaced by a cylo-
pentane ring; both - and -carbocyclic nucleosides are of
considerable interest for the development of therapeutic
agents, such as -abacavir[3] (active against HIV), -enteca-
vir[4] (active against HBV), -noraristeromycin[5] [lacking
the hydroxymethyl substituent, active against human and
Plasmodium falciparum (P. falciparum) recombinant SAH
hydrolase], the non-natural isomers -2Ј,3Ј-dideoxy-
2Ј,3Ј-didehydro-2Ј-fluoroadenosine[6] (-2ЈF-C-d4A, active
against HIV), or -cyclopentenylcytosine[7] (-CPE-C,
active against West Nile virus) (Figure 1).
Figure 1. Selected bioactive carbocyclic nucleosides.
Another alteration to the nucleoside structure that has
resulted in profound biological effects is the modification
of the heterocyclic base, leading to C-nucleosides.[3] Among
them, naturally occurring pseudouridine,[8] showdomycin,[9]
and thiazofurin,[10] have been shown to possess a wide
range of medicinal properties, including antibiotic, antivi-
ral, and antitumor activity (Figure 2). Carbocyclic C-nu-
cleosides, such as carbocyclic showdomycin[11] and carbocy-
clic pyrazofurin A[12] possessing the structural features of
both carbocyclic nucleosides and C-nucleosides, have been
given relatively little attention, although they are chemically
challenging[13] and may possess interesting biological ac-
tivity. Also, the chemistry of benzimidazoles and congeneric
compounds has been of interest as inhibitors of nucleic acid
biosynthesis, as fungicides or insecticides,[14] for characteri-
zation and identification of carbohydrates,[15] but also since
the discovery that 5,6-dimethyl-1-(α--ribofuranosyl)benz-
imidazole was an integral part of the chemical structure of
[a] Institut de Chimie Organique et Analytique, UMR CNRS
6005, Université d’Orléans,
45067 Orléans, France
E-mail: luigi.agrofoglio@univ-orleans.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900950.
Figure 2. Selected bioactive C-nucleosides.
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U. Pradere, H. Kumamoto, V. Roy, L. A. Agrofoglio
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vitamin B2.[16] Recently, Stambasky et al.[37] reported the potassium carbonate in methanol, followed by silylation of
synthesis of a number of artificial aryl-C-nucleosides cap- the obtained derivative with tert-butyldiphenylsilyl chloride
able of π-stacking for artificial expanded genetic infor- (TBDPSCl) gave silylated ether 5 in 84% yield (two steps).
mation systems (AEGIS).
C-Oxime 6 was readily prepared in two steps through the
Most of the known carbocyclic C-nucleosides have been corresponding aldehyde (obtained by glycol cleavage of 5
synthesized as racemic mixtures although a few examples with a catalytic amount of OsO4 in the presence of NaIO4)
of asymmetric syntheses have been reported, but no -car- by addition of hydroxylamine hydrochloride in 74% yield
bocyclic C-nucleosides have been yet described. Therefore, (2 steps). C-Chlorooxime 7 was obtained by C-chlorination
on the basis of the interesting chemical and biological prop- with N-chlorosuccinimide (NCS)[35] and a catalytic amount
erties of C-nucleosides and -carbocyclic nucleosides, it was of pyridine in refluxing CHCl3. After evaporation of the
of interest to report the preparation of hitherto unknown - volatiles, crude product 7 was directly treated with different
carbocyclic C-nucleosides from a C-chlorooxime precursor. α-amino aromatic compounds in EtOH as reported by
Shih[36] to afford the benzoxazolo (8), benzimidazolo (9),
and benzothiazolo (10) derivatives, respectively, in good
yields.
Results and Discussion
General methods for the synthesis of C-nucleosides in-
clude the addition of an organometallic reagent to a ribono-
lactone derivative followed by hemiacetal deoxygen-
ation,[17] the direct introduction of a preformed heterocyclic
base into the anomeric position of a carbohydrate,[18] a Pd0-
mediated coupling reaction,[19] or the construction of the
heterocyclic ring from C-glycosyl derivatives (e.g., nitrile,
thioamide, cyanomethoxyacrylonitrile). Recently, Wamhoff
et al. proposed a novel synthetic approach to purine-like C-
nucleosides from C-glycosidic tosyloximino nitrile precur-
sors.[20] Carbocyclic C-nucleosides have been obtained from
an amide[21] or from a cyanoacetate.[22] A retrosynthetic
analysis indicates that -cyclopentyl carbocyclic C-nucleo-
sides can be prepared by direct cyclocondensation of a de-
sired heterocyclic precursor with a functionalized C-chlo-
rooxime. It has been reported in the literature that α-chlo-
rooximes[23] are versatile compounds for heterocyclic chem-
istry. For the synthesis of -cyclopentyl nucleosides, we se-
lected (–)-cyclopentanol 3 as a chiral intermediate, which
was prepared from chiral -2-cyclopentenone 1, which is
known as a versatile synthon for the syntheses of various
-carbocyclic nucleosides.[24,25] The first practical pro-
cedures to obtain 1 were reported by Jeong et al.[26,27] start-
Scheme 1. Reagents and conditions: (a) vinylmagnesium bromide,
CuBrMe2S, TMSCl, HMPA, THF, 3 h, –78 °C; (b) LiAlH4, THF,
3 h, room temp.; (c) AcOH, DIAD, PPh3, THF, 15 h, room temp.;
(d) K2CO3, MeOH, 1 h, room temp., then TBDPSCl, DMAP, imid-
azole, CH3CN, 15 h, room temp.; (e) OsO4, NaIO4, H2O, MeOH,
acetone, 15 h, room temp., then NH2OH·HCl, NaOAc, EtOH,
CH2Cl2, 2 h, room temp.; (f) NCS, pyridine, CHCl3, 40 °C; (g) 2-
aminophenol, EtOH, 60 °C, 2 h (for 8) or benzene-1,2-diamine,
EtOH, 60 °C, 2 h (for 9) or 2-aminobenzenethiol, EtOH, 60 °C, 2 h
(for 10); (h) 2  HCl, dioxane.
ing from inexpensive -isoascorbic acid, and then by Chu
et al.[28,29] starting from -ribose. Recently, we reported[30]
an optimized synthesis of 1 on the basis of a ring-closing
metathesis reaction.[31]
Thus, treatment of 1 with vinyl Grignard in the presence
of dimethylsulfur copper, as described by Schneller et al.,[32]
gave optically pure cyclopentanone 2 as a single isomer in
78% yield (Scheme 1). The incorporation of a vinyl group
onto a cyclopentyl ring by 1,4-enone addition is known to
be a high-yielding reaction.[33] This reaction is highly sensi-
Interestingly, when 2-aminobenzenethiol was treated
tive to temperature, as a slight increase of the temperature with C-chlorooxime 7, we observed also the formation of
by 3 °C induces an important decrease in the yield. Re- α-isomer 10b. The mechanism of the isomerization is
duction of cyclopentanone 2 with lithium aluminum hy- thought to be as depicted in Scheme 2. Deprotonation of
dride gave α-alcohol 3 in 85% yield. Mitsunobu[34] acyl- H1Ј is followed by an electron push starting from C1Ј to
ation of the secondary alcohol of 3 in the presence of di- give an unsaturated intermediate, which after protonation
isopropyl azodicarboxylate (DIAD) and triphenylphos- led to the α-benzothiazolo compound, minimizing thus the
phane (TPP) led to 4 (90%) with complete inversion of con- interaction with the TBDPS protecting group. Trace
figuration at the C1Ј-carbinyl carbon atom, as confirmed by amounts of the α-isomer (5%) cannot be avoided during
NOESY experiments. Saponification of compound 4 with the reaction, but the two diastereomers 10a and 10b can be
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Preparation of Carbocyclic C-Nucleosides from α-Chlorooxime Precursor
easily separated by chromatography on silica gel. When the Table 1. Acidic deprotection of 10b to 15.
reaction time was increased from 2 to 24 h at 60 °C, α-iso-
mer 10b was isolated in 52% yield, and the β-isomer was
isolated 27%. An increase in the temperature Ͼ60 °C or a
prolonged reaction time Ͼ24 h induced degradation.
Entry Conditions
T [°C]
Observation
1
2
3
4
5
6
2  HCl in dioxane
room temp.
TFA/H2O/EtOH (40:10:50) room temp.
50
partial 15
partial 15
15
no reaction
15
AcOH/H2O (70:30)
room temp.
50
room temp.
1  HCl in Et2O
15
Scheme 2.
Treatment of 8–10a with 2  HCl in dioxane afforded the
desired -carbocyclic C-nornucleosides 11–13, respectively.
Whereas benzimidazolo 9 and benzothiazolo 10a com-
pounds were deprotected in good yields (Ͼ95%), benz-
oxazolo compound 11 was only isolated in 78% yield. This
is due to an aromatic ring opening acidic degradation of 8,
leading to the formation of the carboxylic acid and the
starting α-aminophenol, as depicted in Scheme 3.
Scheme 4.
Conclusions
The nucleosides obtained were fully characterized by
spectroscopic methods. Nuclear Overhauser enhancement
studies confirmed the stereochemistry at C1Ј. Despite the
fact that neither antiviral activities nor toxicities were
found, this reaction would potentially be useful to chemists
seeking to generate libraries of carbocyclic C-nucleosides
bearing modified heterocycles (e.g., 5-aminoisoxazoles, 5-
alkylisoxazoles) for potential biological activities.
Scheme 3.
We attempted to deprotect β-benzothiazolo 10a under a
variety of acidic conditions (Table 1), but α-isomer 10b
never gave desired compound 14; instead unsaturated deriv-
ative 15 was obtained (Table 1).
The mechanism of the formation of unsaturated 15 from
α-isomer 10b is thought to be as that depicted in Scheme 4,
starting with the protonation of the benzothiazol-2-yl
moiety of 10b followed by its deprotonation, leading to the
3H-benzothiazol-2-ylidene analogue (A); subsequent pro-
tonation of the isopropylidene group followed by deproton-
ation led to the hemicetal (B), which is then converted into
15.
Experimental Section
General Remarks: Commercially available chemicals were used as
received. Microwave reactions were carried out with a Biotage Initi-
ator with a maximum power of 300 W and temperatures were mea-
sured by an IR sensor. Reactions were monitored by thin-layer
chromatography (TLC) analysis using silica gel plates (Kieselgel 60
F254). Compounds were visualized by UV irradiation and/or spray-
ing with ethanol solution 2.5% in phosphomolybdic acid, followed
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U. Pradere, H. Kumamoto, V. Roy, L. A. Agrofoglio
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by charring at 150 °C. Column chromatography was performed on
silica gel 60  (0.040–0.063 mm). 1H and 13C NMR spectra were
recorded with a Bruker Avance DPX 250 (1H: 249.88 MHz, 13C:
62.84 MHz) and Varian Inova Unity 400 spectrometer (1H:
399.91 MHz, 13C: 100.54 MHz) in [D6]DMSO or a CDCl3/[D6]-
DMSO mixture. The NMR spectra were recorded at room tem-
perature. The chemical shifts are given in ppm relative to the resid-
ual signal of the solvent, TMS being used as calibration standard
with different deuterated solvents. Evidence of purity was con-
firmed from a proton-decoupled 13C NMR spectrum with a signal-
to-noise ratio sufficient to permit seeing peaks with 5% of the in-
tensity of the strongest peak.
1371, 1064, 700 cm–1. HRMS (ESI): calcd. for C26H34O3NaSi [M
+ Na]+ 445.2175; found 445.2174.
(1R,2R,3R,4R)-1-Aldoxime-4-tert-butyldiphenylsiloxy-2,3-(O-iso-
propylidenedioxy)cyclopentane (6): To a mixture of silyl ether 5
(2.20 g, 5.2 mmol) and NaIO4 (2.23 g, 10.4 mmol) in MeOH was
added acetone, H2O (1:1:1, 200 mL), and OsO4 (820 µL, 2.5% in
tBuOH) at room temperature. After 15 h stirring, the reaction mix-
ture was filtered through Celite, and the filtrate was concentrated
under reduced pressure. CH2Cl2 was added, and the solution was
washed with brine, dried (MgSO4), filtered, and concentrated.
Without further purification, hydroxylamine hydrochloride (1.46 g,
20.8 mmol), NaOAc (2.56 g, 21.3 mmol), and EtOH/CH2Cl2 (1:3,
45 mL) was added at room temperature under positive pressure of
dry argon, and the mixture was stirred for 2 h. Then the reaction
mixture was washed with brine and extracted with CH2Cl2. The
organic layer was dried (MgSO4), filtered, and concentrated. The
residue was purified by silica gel chromatography (petroleum ether/
AcOEt, 3:1) to give 6 (1.69 g, 74%) as an oil as an isomeric mixture
of the oxime (E/Z = 1:1). [α]2D0 = +2.7 (c = 1.4, CH2Cl2). 1H NMR
(400 MHz, CDCl3, E/Z isomers): δ = 7.70–7.62 (m, 12 H, Har and
CH=N-OH), 4.79 (dd, J = 19.7, 5.6 Hz, 2 H, 2-H or 3-H), 4.33 (d,
J = 3.6 Hz, 1 H, 4-H), 2.96–2.90 (m, 1 H, 1-H), 2.18–2.11 (m, 2 H,
5-H), 1.26 (s, 3 H, iPr), 1.25 (s, 3 H, iPr), 1.10 (s, 9 H, tBu) ppm.
13C NMR (100.6 MHz, CDCl3, E/Z isomers): δ = 154.0 (CH=N-
OH), 135.8 (Car), 135.7 (Car), 133.4 (Car), 133.3 (Car), 129.8 (Car),
129.7 (Car), 110.3 (quat., CiPr), 87.1 (2-C or 3-C), 84.2 (2-C or 3-
C), 78.4 (4-C), 45.3 (1-C), 36.4 (5-C), 26.9 (tBu), 26.8 (iPr), 24.2
(1R,2R,3S,4R)-4-Acetyloxy-2,3-(O-isopropylidenedioxy)-1-vinylcyclo-
pentane (4): To a solution of alcohol 3 (1.33 g, 7.2 mmol) in THF
(30 mL) was dropwise added AcOH (0.82 mL, 14.4 mmol), PPh3
(3.78 g, 14.4 mmol), and DIAD (2.86 mL, 14.4 mmol) at 0 °C un-
der positive pressure of dry argon. After 10 min at 0 °C, the reac-
tion mixture was warmed to room temperature and stirred for 15 h.
Then, the reaction mixture was washed with an aqueous saturated
solution of NaHCO3 and extracted with AcOEt. The organic layer
was dried (MgSO4), filtered, and concentrated. The residue was
purified by flash chromatography (petroleum ether/AcOEt, 9:1) to
1
afford 4 (1.47 g, 90%) as an oil. H NMR (400 MHz, CDCl3): δ =
17.3 (J = 10.3, 7.9 Hz, 1 H, CH2=CH), 5.09 (td, J = 17.3, 1.4 Hz,
1 H, CH2=CH), 5.06–5.01 (m, 2 H, CH2=CH and 4-H), 4.53 (d, J
= 6.2 Hz, 1 H, 2-H or 3-H), 4.48 (dd, J = 6.22, 2.8 Hz, 1 H, 2-H
or 3-H), 2.82–2.75 (m, 1 H, 1-H), 2.40 (ddd, J = 13.5, 7.2, 6.1 Hz,
1 H, 5-Ha), 2.04 (s, 3 H, OAc), 1.69 (td, J = 13.9, 4.8 Hz, 1 H, 5-
Hb), 1.47 (s, 3 H, iPr), 1.29 (s, 3 H, iPr) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 170.1 (C=O), 138.9 (CH=CH2), 115.3
(CH=CH2), 111.4 (quat., CiPr), 84.9 (2-C or 3-C), 79.5 (4-C), 48.4
(iPr), 19.0 (tBu) ppm. IR: ν = 3404, 2961, 2923, 1259, 1087, 1017,
˜
797 cm–1. HRMS (ESI): calcd. for C25H33NO4NaSi [M + Na]+
462.2077; found 462.2073.
(1S,2R,3R,4R)-4-tert-Butyldiphenylsiloxy-1-(benzoxazol-2-yl)-2,3-
(O-isopropylidenedioxy)cyclopentane (8): A mixture of 6 (250 mg,
0.566 mmol), N-chlorosuccinimide (77 mg, 0.577 mmol), and pyr-
idine (30 µL) in freshly distilled CHCl3 (8 mL) was heated at 40 °C
for 40 min under positive pressure of dry argon. The reaction mix-
ture was then concentrated and EtOH (16 mL) and α-aminophenol
(127 mg, 1.16 mmol) were added, and the mixture was heated at
60 °C for 2 h under positive pressure of dry argon. The mixture
was diluted in CH2Cl2 and washed with brine, dried (MgSO4), fil-
tered, and concentrated under reduced pressure. The crude was
purified by flash chromatography (petroleum ether/AcOEt, 7:1) to
afford 8 (218 mg, 75%) as an oil. [α]2D0 = +30.8 (c = 0.8, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 7.69 (dd, J = 6.4, 2.5 Hz, 1 H,
Har), 7.54–7.50 (m, 2 H, Har), 7.47–7.43 (m, 3 H, Har), 7.40–7.23
(m, 8 H, Har), 5.60 (dd, J = 5.9, 1.1 Hz, 1 H, 2Ј-H or 3Ј-H), 4.60
(d, J = 5.9 Hz, 1 H, 2Ј-H or 3Ј-H), 4.28 (t, J = 3.1 Hz, 1 H, 4Ј-H),
3.56–3.49 (m, 1 H, 1Ј-H), 2.44–2.34 (m, 2 H, 5Ј-H), 1.39 (s, 3 H,
iPr), 1.30 (s, 3 H, iPr), 0.73 (s, 9 H, tBu) ppm. 13C NMR
(100.6 MHz, CDCl3): δ = 167.2 (C=N), 150.8, 141.4, 135.7, 135.6
and 133.3 (Car), 129.6, 127.6, 127.5, 124.5, 124.1, 119.6 and 110.6
(Car), 110.3 (iPr), 86.8 (2Ј-C or 3Ј-C), 82.4 (2Ј-C or 3Ј-C), 78.2 (4Ј-
C), 44.4 (1Ј-C), 36.2 (5Ј-C), 26.4 (iPr and tBu), 24.2 (iPr), 18.7
(1-C), 35.0 (5-C), 26.7 (iPr), 24.4 (iPr), 21.1 (CH ) ppm. IR: ν =
˜
3
2958, 2926, 2856, 1729, 1271, 1072, 702 cm–1. HRMS (ESI): calcd.
for C12H19O4 [M + H]+ 226.2712; found 226.2707.
(1R,2R,3R,4R)-4-tert-Butyldimethylsiloxy-2,3-(O-isopropylidenedi-
oxy)-1-vinylcyclopentane (5): K2CO3 (1.72 g, 12.4 mmol) was added
to a solution of 4 (1.4 g, 6.2 mmol) in MeOH (20 mL) at room
temperature and stirred for 1 h. Then, the reaction mixture was
neutralized with acetic acid, poured in aqueous saturated
NaHCO3, and extracted with CH2Cl2. The organic layer was dried
with MgSO4, filtered, and concentrated. The residue was dissolved
in MeCN (40 mL) and TBDPSCl (1.88 g, 6.8 mmol), DMAP
(0.84 g, 6.8 mmol), and imidazole (0.46 g, 6.8 mmol) were added at
room temperature under positive pressure of dry argon. After 15 h
stirring, the solution was neutralized with aqueous saturated
NaHCO3 and extracted with AcOEt. The organic layer was dried
with MgSO4, filtered, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (pe-
troleum ether/AcOEt, 30:1) to obtain 5 (2.2 g, 84 %) as an oil.
1
[α]2D0 = +0.9 (c = 1.0, CH2Cl2). H NMR (400 MHz, CDCl3): δ =
7.71–7.65 (m, 4 H, Har), 7.45–7.35 (m, 6 H, Har), 6.04 (ddd, J =
17.3, 10.2, 8.3 Hz, 1 H, CH=CH2), 5.06 (ddd, J = 17.2, 1.6, 1.3 Hz,
1 H, CH=CH2), 5.01 (ddd, J = 10.6, 1.6, 1.1 Hz, 1 H, CH=CH2),
4.53 (d, J = 6.3 Hz, 1 H, 2-H or 3-H), 4.49 (dd, J = 6.3, 2.6 Hz, 1
H, 2-H or 3-H), 4.26 (ddd, J = 5.6, 4.0, 1.6 Hz, 1 H, 4-H), 2.69–
2.59 (m, 1 H, 1-H), 2.05 (ddd, J = 13.0, 7.4, 5.3 Hz, 1 H, 5-Ha),
1.61 (td, J = 13.4, 5.1 Hz, 1 H, 5-Hb), 1.36 (s, 3 H, iPr), 1.25 (s, 3
(tBu) ppm. IR: ν = 2931, 2857, 2361, 1456, 1044, 702 cm–1. HRMS
˜
(ESI): calcd. for C31H35NO4NaSi [M + Na]+ 536.2233; found
536.2234.
(1S,2R,3R,4R)-4-tert-Butyldiphenylsiloxy-1-(benzimidazol-2-yl)-2,3-
(O-isopropylidenedioxy)cyclopentane (9): A mixture of 6 (285 mg,
H, iPr), 1.07 (s, 9 H, tBu) ppm. 13CNMR (100.6 MHz, CDCl3): δ 0.65 mmol), N-chlorosuccinimide (90 mg, 0.66 mmol), and pyridine
= 140.6 (CH=CH2), 135.8 (Car), 133.8 (Car), 133.6 (Car), 129.6 (35 µL) in freshly distilled CHCl3 (6 mL) was heated for 40 min
(Car), 127.6 (Car), 114.5 (CH=CH2), 110.7 (quat., CiPr), 87.6 (2-C
or 3-C), 85.2 (2-C or 3-C), 78.8 (4-C), 49.0 (1-C), 38.2 (5-C), 26.9 solution under reduced pressure, EtOH (22 mL) and α-phenylened-
(tBu), 26.8 (iPr), 24.5 (iPr), 19.1 (tBu) ppm. IR: ν = 2931, 2857, iamine (176 mg, 1.63 mmol) were added, and the mixture was
under positive pressure of dry argon. After concentration of the
˜
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Preparation of Carbocyclic C-Nucleosides from α-Chlorooxime Precursor
heated at 60 °C for 2 h under positive pressure of dry argon. The
reaction mixture was diluted in CH2Cl2 and washed with brine,
dried (MgSO4), filtered, and concentrated under reduced pressure.
The crude was purified on silica gel chromatography (petroleum
ether/AcOEt, 2:1) to afford 9 (278 mg, 85%) as a foam. [α]2D0 = +9.7
(c = 1.0, CH2Cl2). 1H NMR (400 MHz, CDCl3): δ = 10.50 (s, 1 H,
NH), 7.77–7.65 (m, 3 H, Har), 7.62 (dd, J = 8.00, 1.32 Hz, 2 H,
Har), 7.50–7.35 (m, 6 H, Har), 7.24–7.05 (m, 3 H, Har), 4.91 (d, J
= 5.6 Hz, 1 H, 2Ј-H or 3Ј-H), 4.59 (d, J = 5.6 Hz, 1 H, 2Ј-H or 3Ј-
H), 4.53 (d, J = 4.5 Hz, 1 H, 4Ј-H), 3.75 (d, J = 8.7 Hz, 1 H, 1Ј-
H), 2.56 (ddd, J = 14.6, 8.7, 5.5 Hz, 1 H, 5Ј-Ha), 2.09 (d, J =
14.6 Hz, 1 H, 5Ј-Hb), 1.38 (s, 3 H, iPr), 1.19 (s, 3 H, iPr), 1.16 (s,
9 H, tBu) ppm. 13C NMR (100.6 MHz, CDCl3): δ = 155.5 (C=N),
135.8, 135.7, 132.6, 132.4, 130.2 (2 C) and 128.0 (2 C, Car), 110.8
(iPr), 87.6 (2Ј-C or 3Ј-C), 85.6 (2Ј-C or 3Ј-C), 80.1 (4Ј-C), 46.3 (1Ј-
C), 36.0 (5Ј-C), 27.2 (tBu), 26.6 and 24.2 (iPr), 19.2 (tBu) ppm. IR:
CDCl3): δ = 170.6 (C=N), 152.6, 135.6, 135.4, 133.4 (2 C), 129.8
(2 C), 127.7 (2 C), 125.7, 124.6, 122.6 and 121.3 (Car), 110.9 (CiPr),
86.8 (2Ј-C), 80.8 (3Ј-CЈ), 76.1 (4Ј-C), 46.4 (1Ј-C), 37.3 (5Ј-C), 26.9
(tBu), 25.7 (iPr), 23.9 (iPr), 19.1 (tBu) ppm. IR: ν = 2930, 1428,
˜
1162, 1066 cm–1. HRMS (ESI): calcd. for C31H36NO3SSi [M +
H]+ 530.2185; found 530.2195.
(1S,2R,3S,4R)-1-Benzoxazol-2-yl-cyclopentane-2,3,4-triol (11): To a
1,4-dioxane (3 mL) solution of 8 (144 mg, 0.28 mmol) was added
2  HCl (1 mL) at room temperature, and the reaction mixture was
stirred for 48 h. Then, NaHCO3 was added, and the solution was
evaporated to dryness. The crude was purified by flash chromatog-
raphy (CH2Cl2/MeOH, 5:1) to give 11 (48 mg, 78%) as an amorph-
ous solid. [α]2D0 = +31.2 (c = 0.2, CH3OH). 1H NMR (400 MHz,
CD3OD): δ = 7.77 (dd, J = 8.0, 1.5 Hz, 1 H, Har), 7.00–6.93 (m, 1
H, Har), 6.88–6.75 (m, 2 H, Har), 4.32 (dd, J = 8.0, 4.9 Hz, 1 H,
2Ј-H), 4.02 (ddd, J = 7.2, 4.7, 2.9 Hz, 1 H, 4Ј-H), 3.83 (dd, J = 4.7,
2.9 Hz, 1 H, 3Ј-H), 2.97 (dd, J = 17.8, 8.4 Hz, 1 H, 1Ј-H), 2.43
(ddd, J = 13.9, 9.6, 7.0 Hz, 1 H, 5Ј-Ha), 1.80 (ddd, J = 13.6, 8.5,
4.7 Hz, 1 H, 5Ј-Hb) ppm. 13C NMR (100.6 MHz, CD3OD): δ =
175.6 (C=N), 149.2, 127.5, 126.3, 123.1, 120.6 and 116.9 (Car), 79.7
(3Ј-C), 76.5 and 76.2 (2Ј-C and 4Ј-C), 50.0 (1Ј-C), 34.4 (5Ј-C) ppm.
ν = 2930, 2856, 1737, 1426, 1042, 700 cm–1. HRMS (ESI): calcd.
˜
for C31H37N2O3Si [M + H]+ 513.2574; found 513.2560.
(1S,2R,3R,4R)-4-tert-Butyldiphenylsiloxy-1-(benzothiazol-2-yl)-2,3-
(O-isopropylidenedioxy)cyclopentane (10a): A mixture of 6 (255 mg,
0.577 mmol), N-chlorosuccinimide (78.6 mg, 0.589 mmol), and pyr-
idine (30 µL) in freshly distilled CHCl3 (8 mL) was heated and
stirred during 40 min under positive pressure of dry argon. The
solvent was evaporated, then EtOH (16 mL) and α-aminothi-
ophenol (148 mg, 1.18 mmol) were added, and the mixture was
heated at 60 °C for 2 h under positive pressure of dry argon. The
reaction mixture was diluted in CH2Cl2 and washed with brine,
dried (MgSO4), filtered, and concentrated under reduced pressure.
The crude was purified on silica gel chromatography (petroleum
ether/AcOEt, 7:1) to afford 10b (15 mg, 5 %) and 10a (229 mg,
75%) as a solid. M.p. 107–109 °C. [α]2D0 = +25.7 (c = 0.8, CH2Cl2).
1H NMR (400 MHz, CDCl3): δ = 8.01–7.97 (m, 1 H, Har), 7.83–
7.79 (m, 1 H, Har), 7.60–7.56 (m, 2 H, Har), 7.49–7.29 (m, 10 H,
Har), 7.23 (t, J = 7.4 Hz, 2 H, Har), 5.44 (dd, J = 6.2, 2.6 Hz, 1 H,
2Ј-H or 3Ј-H), 4.63 (d, J = 6.19 Hz, 1 H, 2Ј-H or 3Ј-H), 4.34–4.31
(m, 1 H, 4Ј-H), 3.62 (ddd, J = 7.9, 5.4, 2.7 Hz, 1 H, 1Ј-H), 2.45
(ddd, J = 13.0, 7.8, 5.0 Hz, 1 H, 5Ј-Ha), 2.33–2.26 (ddd, J = 13.5,
5.1, 7.4 Hz, 1 H, 5Ј-Hb), 1.42 (s, 3 H, iPr), 1.31 (s, 3 H, iPr), 0.84
(s, 9 H, tBu) ppm. 13C NMR (100.6 MHz,CDCl3): δ = 173.0
(C=N), 153.1, 135.7, 135.6, 135.1, 133.5, 133.4, 129.6, 129.5, 127.5,
127.4, 125.8, 124.6, 122.7 and 121.3 (Car), 111.2 (CiPr), 86.9 (2Ј-C
or 3Ј-C), 83.8 (2Ј-C or 3Ј-CЈ), 78.3 (4Ј-C), 49.3 (1Ј-C), 39.4 (5Ј-C),
IR: ν = 3331, 2955, 2925, 1658, 1384, 1196 cm–1. HRMS (ESI):
˜
calcd. for C12H14NO4 [M + H]+ 236.0936; found 236.0944.
(1S,2R,3S,4R)-1-Benzimidazol-2-yl-cyclopentane-2,3,4-triol (12): To
a 1,4-dioxane (3 mL) solution of 9 (92 mg, 0.179 mmol) was added
2  HCl (1 mL) at room temperature, and the reaction mixture was
stirred for 48 h. Then, NaHCO3 was added, and the solution was
evaporated to dryness. The crude was purified by flash chromatog-
raphy (CH2Cl2/MeOH, 5:1) to give 12 (40 mg, 95%) as an amorph-
ous solid. [α]2D0 = +72.6 (c = 0.6, CH3OH). 1H NMR (400 MHz,
CD3OD): δ = 7.57–7.46 (m, 2 H, Har), 7.23–7.13 (m, 2 H, Har),
4.42 (dd, J = 8.1, 5.1 Hz, 1 H, 2Ј-H), 4.11 (ddd, J = 7.2, 5.3, 3.1 Hz,
1 H, 4Ј-H), 3.92 (dd, J = 5.0, 3.1 Hz, 1 H, 3Ј-H), 3.40 (dd, J =
17.6, 9.2 Hz, 1 H, 1Ј-H), 2.64 (ddd, J = 13.8, 9.3, 7.1 Hz, 1 H, 5Ј-
Ha), 1.88 (ddd, J = 14.4, 9.4, 5.3 Hz, 1 H, 5Ј-Hb) ppm. 13C NMR
(100.6 MHz, CD3OD): δ = 158.3 (C=N), 139.8, 139.7, 123.3 and
115.5 (2 C, Car), 79.5 (3Ј-C), 77.5 (2Ј-C), 76.8 (4Ј-C), 44.0 (1Ј-C),
36.8 (5Ј-C) ppm. IR: ν = 3314, 2920, 1454, 1116, 1053 cm–1. HRMS
˜
(ESI): calcd. for C12H15N2O3 [M + H]+ 235.1083; found 235.1073.
(1S,2R,3S,4R)-1-Benzothiazol-2-yl-cyclopentane-2,3,4-triol (13): To
a 1,4-dioxane (3 mL) solution of 10a (104 mg, 0.196 mmol) was
added 2  HCl (1 mL) at room temperature, and the reaction mix-
ture was stirred for 48 h. Then, the reaction mixture was neutral-
ized with NaHCO3, and the solution was evaporated to dryness.
The crude was purified by flash chromatography (CH2Cl2/MeOH,
5:1) to give 13 (48 mg, 97%) as an amorphous solid. [α]2D0 = +72.5
26.7 (iPr), 26.5 (tBu), 24.5 (iPr), 18.9 (tBu) ppm. IR: ν = 2972,
˜
2925, 1427, 1042 cm–1. HRMS (ESI): calcd. for C31H36NO3SSi [M
+ H]+ 530.2185; found 530.2195.
(1R,2R,3R,4R)-4-tert-Butyldiphenylsiloxy-1-(benzothiazol-2-yl)-2,3-
(O-isopropylidenedioxy)cyclopentane (10b): A mixture of 6 (93 mg,
0.210 mmol), N-chlorosuccinimide (29 mg, 0.214 mmol), and pyr-
idine (10 µL) in freshly distilled CHCl3 (3 mL) was heated for
40 min under positive pressure of dry argon. After evaporation of
all of volatiles, EtOH (6 mL) and α-aminothiophenol (54 mg,
0.43 mmol) were added, and the mixture was heated at 60 °C for
24 h under positive pressure of dry argon. The solvent was evapo-
rated to dryness and the crude was purified by silica gel chromatog-
raphy (petroleum ether/AcOEt, 7:1) to give 10a (30 mg, 27%) and
10b (58 mg, 0.109 mmol, 52%) as an oil. [α]2D0 = +39.1 (c = 0.8,
1
(c = 0.4, CH3OH). H NMR (400 MHz, CD3OD): δ = 7.99–7.88
(t, J = 7.8 Hz, 2 H, Har), 7.52–7.45 (td, J = 7.5, 1.2 Hz, 1 H, Har),
7.43–7.36 (m, J = 7.5, 1.2 Hz, 1 H, Har), 4.41 (dd, J = 8.2, 4.9 Hz,
1 H, 2Ј-H), 4.12 (ddd, J = 7.2, 4.7, 2.8 Hz, 1 H, 4Ј-H), 3.92 (dd, J
= 4.7, 2.8 Hz, 1 H, 3Ј-H), 3.63 (td, J = 9.1, 8.4 Hz, 1 H, 1Ј-H), 2.74
(ddd, J = 13.9, 9.5, 7.0 Hz, 1 H, 5Ј-Ha), 1.95 (ddd, J = 13.6, 9.0,
4.5 Hz, 1 H, 5Ј-Hb) ppm. 13C NMR (100.6 MHz, CD3OD): δ =
176.7 (C=N), 154.1, 136.2, 127.3, 126.2, 123.1 and 122.9 (Car), 79.6
(3Ј-C), 79.0 (2Ј-C), 76.5 (4Ј-C), 48.7 (1Ј-C), 38.3 (5Ј-C) ppm. IR:
ν = 3316, 2922, 1657, 1113, 1048 cm–1. HRMS (ESI): calcd. for
˜
1
CH2Cl2). H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.06 Hz,
C12H14NO3S [M + H]+ 252.0694; found 252.0687.
1 H, Har), 7.84 (d, J = 7.98 Hz, 1 H, Har), 7.69–7.62 (m, 4 H, Har),
7.48–7.31 (m, 8 H, Har), 5.03 (t, J = 5.0 Hz, 1 H, 3Ј-H), 4.58 (dd,
(3R,4R)-1-Benzothiazol-2-yl-cyclopent-1-ene-3,4-diol (15): A solu-
J = 5.3, 1.4 Hz, 1 H, 2Ј-H), 4.30 (d, J = 3.4 Hz, 1 H, 1Ј-H), 4.20 tion of protected nucleoside 10b (30 mg, 0.056 mmol) in 1  HCl
(td, J = 13.0, 5.5 Hz 1 H, 4Ј-H), 2.25 (td, J = 13.0, 3.60 Hz, 1 H,
5Ј-Ha), 2.06 (td, J = 13.0, 3.6 Hz, 1 H, 5Ј-Hb), 1.39 (s, 3 H, iPr),
1.24 (s, 3 H, iPr), 1.09 (d, 9 H, tBu) ppm. 13C NMR (100.6 MHz,
(1 mL) in Et2O was stirred for 18 h. Then, the reaction mixture was
neutralized with NaHCO3, and the organic layer was dried, filtered,
and concentrated under reduced pressure. The residue was purified
Eur. J. Org. Chem. 2010, 749–754
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
753

U. Pradere, H. Kumamoto, V. Roy, L. A. Agrofoglio
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Received: August 20, 2009
Published Online: December 9, 2009
754
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 749–754