Synthesis and O-phosphorylation of 3,3,4,4-tetrafluoroaryl-C-nucleoside analogues

Article abstract of DOI:10.1039/b922442d

Enantioenriched tetrafluorinated aryl-C-nucleosides were synthesised in four steps from 1-benzyloxy-4-bromo-3,3,4,4-tetrafluorobutan-2-ol. The presence of the tetrafluorinated ethylene group is compatible with O-phosphorylation of the primary alcohol, as

Full text of DOI:10.1039/b922442d

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthesis and O-phosphorylation of 3,3,4,4-tetrafluoroaryl-C-nucleoside
analogues†
Laurent Bonnac,a Sarah E. Lee,a Guy T. Giuffredi,a Lucy M. Elphick,b Alexandra A. Anderson,b
Emma S. Child,b David J. Mannb and Ve´ronique Gouverneur*a
Received 28th October 2009, Accepted 5th December 2009
First published as an Advance Article on the web 25th January 2010
DOI: 10.1039/b922442d
Enantioenriched tetrafluorinated aryl-C-nucleosides were synthesised in four steps from
1-benzyloxy-4-bromo-3,3,4,4-tetrafluorobutan-2-ol. The presence of the tetrafluorinated ethylene group
is compatible with O-phosphorylation of the primary alcohol, as demonstrated by the successful
preparation of the tetrafluorinated naphthyl-C-nucleotide.
In contrast to most natural nucleosides, the sugar moiety and
aglycon of C-nucleosides are united by a C–C bond, a structural
characteristic accounting for their advantageous resistance to
hydrolytic and enzymatic cleavage. Although some derivatives
have been isolated from natural sources (e.g. pseudouridine, 1-
methylpseudouridine and 2¢-O-methylpseudouridine),1 most C-
nucleosides are synthetic compounds tailored to fulfil specific
biological functions. In addition to their chemotherapeutic proper-
ties (e.g. antibiotic, antiviral or anticancer activity), C-nucleosides
have proved useful for the development of universal bases and the
synthesis of triplex DNA constructs for gene therapy.2
Fig. 1 Monofluoro-, difluoro- and tetrafluoro-C-nucleosides.
carbohydrates may be significantly modulated by extensive re-
placement of CHOH groups by CF2 groups. For example, the
hexafluoropyranose 1 was shown to cross the erythrocyte mem-
brane at a rate significantly superior to glucose, an acceleration
effect resulting from enhanced affinity for the transporter protein.7
This observation fuelled an interest in the preparation of heavily
fluorinated sugars. The de novo asymmetric synthesis of the
tetrafluoropyranose 2, and more recently of the structurally related
derivatives 3 and 4, was validated by Linclau et al. (Fig. 2).8 This
background information led us to believe that the synthesis of
tetrafluorinated C-nucleosides III is of interest and within reach,
offering the prospect of understanding their physicochemical and
biological properties. Herein, we describe the first synthesis of
tetrafluoro-C-nucleosides. We also demonstrate that these tetraflu-
orinated C-nucleosides are amenable to O-phosphorylation.
Since the properties of these compounds may be tuned upon
structural modification, the synthesis of C-nucleosides is an active
research area. Structural diversity emerges from the aglycon motif
and/or the carbohydrate unit. Representative examples of sugar-
modified C-nucleosides are the aza-analogues Immucillin-H and
Immucillin-G, known to act as transition state analogue inhibitors
of purine nucleoside phosphorylase, a therapeutic target for the
control of T-cell proliferation.3
To date, a very limited number of C-nucleosides featuring
fluorine substituents on the sugar moiety have been prepared.
Notable exceptions are the isostere of the well-documented
antiviral agent 1-(2-deoxy-2-fluoro-b-D-arabinofuranosyl)thy-
mine I and the aza-derivative (1S)-1-(9-deazahypoxanthin-9-
yl)-1,2,4-trideoxy-2,2-difluoro-1,4-imino-D-erythro pentitol) II, a
fluorinated analogue of Immucillin-H.4 Our research activity in
fluorine chemistry5 and a programme aimed at applying a chemical
genetic approach for the identification of kinase substrates6 led
us to explore synthetic routes towards the novel sugar-modified
tetrafluorinated aryl-C-nucleosides III for biological investiga-
tions (Fig. 1). We opted for aryl-C-nucleosides, as the aryl base
analogues are particularly useful due to their advantageous base
stacking ability.
Fig. 2 Tetrafluorinated carbohydrate analogues.
DiMagno and co-workers launched the concept of “polar
hydrophobicity”, and suggested that the binding affinities of
Based on literature precedents reporting the preparation of non-
fluorinated C-nucleosides,9 we opted to prepare the non-natural
motif III by direct attachment of the aglycon to the tetrafluorinated
sugar precursor. This strategy was selected in preference to an
approach based on the introduction of a functional group at
the anomeric position of the sugar analogue, followed by the
construction of the aglycon motif, since it is documented that for
non-fluorinated precursors, this more lengthy synthetic route may
aUniversity of Oxford, Chemistry Research Laboratory, Oxford, United
Kingdom OX1 3TA. E-mail: Veronique.gouverneur@chem.ox.ac.uk;
Fax: +44 (0)1865275644; Tel: +44 (0)1865275644
bImperial College London, Cell Cycle Laboratory, London, United Kingdom
SW7 2AZ
1
† Electronic supplementary information (ESI) available: H, 13C, 19F and
31P NMR spectra of all new compounds. See DOI: 10.1039/b922442d
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Table 1 Aglycone attachment
suffer from poor stereoselectivity. In our retrosynthetic analysis,
weoptedfor anesterificationoftheknowntetrafluorinatedalcohol
(2R)-5 for the attachment of the aglycon motif, followed by a
cyclization and dehydroxylation event.10 Points of interest are
the possible impact of the presence of tetrafluoroethylene group
on the feasibility and stereochemical outcome of the reductive
dehydroxylation, and on the reactivity of the primary alcohol
within III if further functionalization is required (Scheme 1).
Entry
1
Ar-
Procedure
A
Product
Yield (%)a
97
6a
6b
2
3
A
B
94
87
6c
6d
6e
Scheme 1 Retrosynthetic scheme.
The racemic alcohol ( )-5 was synthesized to validate, optimise,
and delineate the scope and limitation of the proposed synthetic
sequence. The synthesis of (2R)-5 was performed according to
literature procedures.8a This material will serve as the key precursor
for the synthesis of enantioenriched tetrafluoro-C-nucleosides.
Our studies began with the attachment of the aglycon motif to
( )-5. The esterifications were performed in dichloromethane using
Et3N and DMAP for acyl chlorides, or using DCC and DMAP
for carboxylic acids. All reactions were high yielding (entries 1–5,
Table 1).
4
5
B
96
57
A
a Isolated yield.
Esters 6a–e were subjected to bromine–lithium exchange with
MeLi at low temperature, a process triggering ring closure.
The resulting cyclized lactols 7a–e were used unpurified for
the subsequent reduction (Table 2). Pleasingly, the Lewis acid-
promoted reductive dehydroxylation with triethylsilane gave 8a–
c in moderate yields, with the b-anomers being formed pre-
dominantly (d.r. up to 5 : 1) (entries 1–3, Table 2).11 Attempts
to improve the b : a ratio using triisopropylsilane instead of
triethylsilane were not successful. The relative stereochemistry of
Table 2 Cyclization and dehydroxylation of ( )-6a–e
1
8a was assigned based on H NMR NOE experiments, and by
Entry
Ester
Product
Yield (%)a
b : a ratio
analogy with 8a for 8b–c. For esters 6d and 6e, the cyclization was
found to be successful, but the reduction did not proceed. The
tetrafluorinated tetrahydrofuran-2-ols 7d and 7e were isolated as
a mixture of anomers (~1 : 1) in 97% and 60% yield, respectively
(entries 4 and 5, Table 2). The failure of 7d and 7e to undergo
reductive dehydroxylation indicates that the presence of the
electron withdrawing groups on both the sugar and aglycon motifs
prevents the formation of the putative oxonium intermediate.
The C-nucleosides 8a–c engaged as diastereomeric mixtures
were deprotected in good yields with a large excess of NaI and
trimethylsilyl chloride in acetonitrile, or using boron tribromide
in dichloromethane. The debenzylation of 7d and 7e delivered
the tetrafluorotetrahydro-2H-pyrano-2,5-diols 10d and 10e in 80%
and 74% yield, respectively (Table 3).12
1
2
3
4
5
( )-6a
( )-6b
( )-6c
( )-6d
( )-6e
( )-8a
( )-8b
( )-8c
( )-7d
( )-7e
60
63
77
97
60
5 : 1b
4 : 1b
2 : 1b/5 : 1c
1.2 : 1b
1.1 : 1b
a Isolated yield. b Determined by 1H NMR on crude product. c Determined
by 1H NMR after purification.
the availability of anomerically pure C-nucleoside, a separation
process was programmed after reductive dehydroxylation. Model
compounds 9a and 9b were chosen for this study. Compound
(2R)-58a was subjected to esterification, cyclization and reduction.
Enantiomeric excesses were measured by chiral stationary phase
HPLC on (2R)-5, (2R,5S)-8a and (2R,5S)-8b, and were found to
be 93%, 90% and 89%, respectively. In order to identify which step
may be responsible for the slight erosion of enantiomeric excess,
Having validated a synthetic route to ( )-9a–c, we next examined
the synthesis of the corresponding enantioenriched tetrafluoro-C-
nucleosides. Since the synthetic value of this chemistry will rely on
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Table 3 Deprotection of ( )-8a–c and ( )-7d and ( )-7e
Table 4 Separation of anomers upon acetylation of 9a and 9b
Entry
Alcohol
Products
Yield (%)
1
2
9a
(2R,5S)-11a
(2R,5R)-11a
(2R,5S)-11b
(2R,5R)-11b
41
5
88
5
b : a ratio 5 : 1
9b
b : a ratio 4 : 1
Table 5 Deacetylation of 11a and 11b
Entry
Starting material
Procedure
Product
Yield (%)
1
2
3
4
5
( )-8a
( )-8b
( )-8c
( )-7d
( )-7e
E
E
( )-9a
( )-9b
( )-9c
( )-10d
( )-10e
90
98
69
80
74
BBr3, CH2Cl2
E
E
ee measurement after the esterification was undertaken on (2R)-
6a, and was found to be 89% (Fig. 3). These data indicate that
detectable epimerization was observed upon esterification under
our reaction conditions. Qing et al.13 and Linclau et al.8c have
discussed this issue of epimerization when benzylating or esteri-
fying structurally related substrates featuring either an electron-
withdrawing gem-difluoromethylene or tetrafluoroethylene group
adjacent to a carbinol.
Entry
Acetate
Product
Yield (%)
1
2
3
4
(2R,5S)-11a
(2R,5R)-11a
(2R,5S)-11b
(2R,5R)-11b
(2R,5S)-9a
(2R,5R)-9a
(2R,5S)-9b
(2R,5R)-9b
77
96
97
83
With a new class of C-nucleosides in hand, we next studied
the impact of the tetrafluoroethylene motif on the reactivity
of the primary alcohol. We were particularly interested in O-
phosphorylation, as bioactivation through phosphorylation is
a key step in cellular nucleoside metabolism. In addition, the
tetrafluorinated C-nucleoside triphosphates have the potential to
become valuable chemical probes for elucidating and validating
drug targets in the field of chemical genetics. Triphosphorylation
of (2R,5S)-9b was performed in a one-pot three-step proce-
dure using phosphoryl chloride and a catalytic amount of 1,8-
Fig. 3 Asymmetric synthesis of 8a and 8b.
R
At this stage we sought to separate the diastereomers to
access anomerically pure compounds. The separation of the
anomers of both the benzyl-protected C-nucleosides (2R,5S)-8a
and (2R,5S)-8b, and the free alcohols (2R,5S)-9a and (2R,5S)-9b
was unsuccessful by silica gel column chromatography (normal
and reverse phase), preparative TLC or HPLC. Satisfyingly, upon
acetylation, the anomers of both (2R,5S)-11a and (2R,5S)-11b
could be separated by careful column chromatography (Table 4).
Deacetylation with sodium methoxide delivered the anomeri-
cally pure C-nucleosides (2R,5S)-9a and (2R,5S)–9b, and (2R,5R)-
9a and (2R,5R)-9b in high yields (Table 5).
bis(dimethylamino)naphthalene (proton spongeꢀ) in THF. This
first step was completed within 24 h at rt, a reaction time
much longer than would be necessary for the O-phosphorylation
of non-fluorinated analogues (usually complete within 2 h at
0 ◦C). Pleasingly, the crude dichlorophosphate could be converted
into the triphosphate (2R,5S)-12b by successive treatment with
pyrophosphate (PPi, tributylammonium salt) in the presence of
nBu3N (24 h) followed by an excess of 0.1 M triethylammonium
bicarbonate (TEAB) buffer (pH 7.5) (48 h). The triphosphate was
purified by reverse phase HPLC and was isolated in 60% yield as
the triethylammonium salt (Scheme 2).
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was achieved using UV fluorescence (254 nm) and KMnO4 stain.
Column chromatography was carried out over Merck silica gel
C60 (40–60 mm). Reverse phase HPLC was performed using a
Dionex P680 pump with UVD340U detector and a Phenomenex
˚
Jupiter 10m; proteo 90 A 250 ¥ 21.2 mM column. Compounds
were named according to IUPAC nomenclature.
General procedure A: esterification using an acid chloride
Scheme 2 Triphosphorylation of (2R,5S)-9b.
The relevant acid chloride (1.2 eq.) was added to a solution of
alcohol 5 (1 eq.), triethylamine (2.2 eq.) and DMAP (0.1 eq.)
in CH2Cl2 (0.2 M) at room temperature, and the reaction was
stirred for 16 h before removal of the solvent. Purification by
column chromatography (pet. ether 40–60◦/Et2O, 90 : 10) afforded
the corresponding ester 6 as a colourless oil.
Conclusions
In summary, we have validated the first asymmetric synthesis
of a new class of aryl-C-nucleosides incorporating a tetra-
fluoroethylene motif. The first enantiomerically enriched 3,3,4,4-
tetrafluoroaryl-C-nucleotide was also successfully prepared as
a single anomer. Despite successful separation of anomers at
a late stage, there is still opportunity for the development of
more stereoselective synthetic routes to these tetrafluorinated-C-
nucleosides.
General procedure B: esterification using an acid
The relevant carboxylic acid (1.1 eq.) was added to a solution
of alcohol 5 (1 eq.), DCC (1.1 eq.) and DMAP (0.1 eq.) in
CH2Cl2 (0.2 M) at room temperature, and the reaction was stirred
for 16 h before removal of the solvent. Purification by column
chromatography (pet. ether 40–60◦/Et2O, 90 : 10) afforded the
corresponding ester 6 as a colourless oil.
Experimental
General experimental details
1
All H NMR spectra were recorded in deuterated solvents using
General procedure C: cyclisation
Bruker DPX200, DPX250, DPX400, AV400 and AV500 spectrom-
eters. 13C NMR spectra were recorded in deuterated solvents using
Bruker DPX400, AV400 and AV500 spectrometers with a carbon-
13 cryoprobe. 19F spectra (both with and without proton decou-
pling) were recorded on a Bruker AVANCE AV400 spectrometer.
31P spectra were recorded on a Bruker DPX250 spectrometer.
NOE difference experiments were performed at 500 MHz on non-
degassed solutions with saturation times totalling 5 s. These were
performed with frequency cycling between the individual lines
within each multiplet to ensure more even suppression of the
wide multiplet structures. 1H and 13C NMR spectra are reported
as chemical shifts (d) in parts per million (ppm) relative to the
solvent peak using the Bruker internal referencing procedure
(edlock). 19F NMR spectra are referenced relative to CFCl3 in
CDCl3. 31P NMR spectra are referenced relative to H3PO4 as an
external standard. Coupling constants (J) are reported in units
of hertz (Hz). The following abbreviations are used to describe
multiplicities, s = singlet, d = doublet, t = triplet, q = quartet,
br = broad m = multiplet. Low and high resolution mass spectra
were recorded on Bruker MicroTof spectrometer using positive or
negative electrospray ionization (ESI+/ESI-). Optical rotations
were determined on a Perkin Elmer 241 polarimeter in a 1 dm cell.
[a]D Values are given in 10-1 deg cm2 g-1. IR spectra were recorded
as thin films on NaCl plates, neat or in solution in CHCl3 on a
Bruker Tensor 27 FTIR spectrometer. Absorptions are measured
in wavenumbers (cm-1) and only peaks of interest are reported.
UV spectra were recorded as solutions in methanol or water on
a Perkin Elmer Lambda 25 UV/VIS spectrometer. Absorptions
are measured in wavelength (nm) and only maxima are reported.
All reactions requiring anhydrous conditions were conducted in
dried apparatus under an inert atmosphere of argon or nitrogen.
Solvents were dried and purified before use according to standard
procedures. All reactions were monitored by TLC using Merck
Kiesegel 60 F254 plates. Visualizations of the reaction components
MeLi (1.6 M in Et2O, 1 eq.) was added dropwise over 60 min to a
solution of ester 6 (1 eq.) in THF (0.1 M) at -78 ◦C. The reaction
was stirred for 1 h at -78 ◦C, then allowed to warm to room
temperature slowly over 3 h. After dilution with Et2O (100 mL)
and addition of NaHCO3 (100 mL sat. aq.), the suspension was
stirred for 15 min. The organic layer was dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. Starting materials were
removed by filtration through a silica pad (pet. ether 40–60◦/Et2O,
90 : 10); products were eluted in Et2O to afford the crude material
of the corresponding furanol 7.
General procedure D: dehydroxylation
BF3OEt2 (2 eq.) and Et3SiH (2 eq.) were added to a solution
of crude furanol 7 in CH2Cl2 (0.2 M), dropwise at -78 ◦C. The
reaction mixture was allowed to slowly warm to room temperature
and stirred for 16 h. After dilution with Et2O (100 mL) and
addition of NaHCO3 (100 mL sat. aq.), the suspension was
stirred for 15 min. The organic layer was dried over anhydrous
Na2SO4, filtered and concentrated in vacuo. Purification by column
chromatography (pet. ether 40–60◦/Et2O, 95 : 5) afforded the
corresponding benzyl-protected C-nucleoside 8 as a mixture of
diastereomers.
General procedure E: debenzylation
NaI (10 eq.) and chlorotrimethylsilane (5 eq.) were added to a
solution of benzyl-protected C-nucleoside 8 (1 eq.) in acetonitrile
(0.08 M) at room temperature and the reaction mixture was stirred
in the dark for 3 d. Aqueous ammonia (5 mL mmol-1) was added
and the reaction mixture was stirred for 15 min, before removal
of the solvent in vacuo. Purification by column chromatography
(pet. ether 40–60◦/Et2O, 50 : 50) afforded the corresponding
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C-nucleoside 9 as either a colourless oil or an amorphous white
solid.
11.2, 7.5 Hz, CHBOBn); 13C NMR (100 MHz, CDCl3): d 165.1
(CO2), 137.2 (CPh), 134.3 (C-2¢), 133.8 (C-10¢), 131.5 (C-9¢), 130.8
(C-4¢), 128.6 (C-4¢), 128.4 (CPh), 128.2 (C-6¢/C-7¢), 127.9 (CPh),
127.6 (CPh), 126.4 (C-6¢/C-7¢), 125.6 (C-8¢), 125.2 (C-1¢), 124.5 (C-
3¢), 116.8 (tt, J = 313, 39 Hz, CF2Br), 113.5 (ddt, J = 263, 256,
32 Hz, CF2), 73.4 (CH2Ph), 67.7 (dd, J = 30, 22 Hz, CHOR), 66.5
General procedure F: acetylation
Pyridine (1.2 eq.) and Ac2O (1.2 eq.) were added sequentially
to a solution of C-nucleoside 9 (1 eq.) in Et2O (3 M) at room
temperature. The reaction mixture was stirred for 16 h before
removal of the solvents in vacuo. Purification by column chro-
matography (pet. ether 40–60◦/Et2O/CH2Cl2, 90 : 5 5) afforded
the corresponding acetyl protected C-nucleoside 11 as an amor-
phous white solid.
1
(CH2OBn); 19F { H} NMR (376 MHz, CDCl3): d -63.9 (2F, t, J =
4 Hz, CF2Br), -113.6 (1F, dt, J = 273 Hz, CF2A), -119.0 (1F, dt,
273, 4 Hz, CF2B); HRMS (ESI+) Calcd for C22H17BrF4O3 [M +
Na]+: 507.0189, found 507.0194.
(1-(Benzyloxy)-4-bromo-3,3,4,4-tetrafluorobutan-2-yl
2,6-dimethoxynicotinate ( )-6c
General procedure G: deacetylation
Following general procedure B, using 2,6-dimethoxypyridine-3-
carboxylic acid (0.30 g, 1.7 mmol) and alcohol ( )-5 (0.50 g,
1.5 mmol), ester ( )-6c was isolated as a colourless oil (0.65 g,
NaOMe (0.01 eq.) was added to a solution of acetyl-protected
C-nucleoside 11 (1 eq.) in MeOH (3 M) at room temperature.
The reaction mixture was stirred for 20 min before addition of
H+-Dowex 50WX8 100-200. Filtration and removal of the solvent
under reduced pressure afforded the corresponding C-nucleoside
9 as an amorphous white solid.
-1
=
1.3 mmol, 87%.). IR (neat, cm ): n 3059, 2951 (C–H), 1734 (C O);
1H NMR (400 MHz, CDCl3): d 8.17 (1H, d, J = 8.5 Hz, H-6¢),
7.40-7.25 (5H, m, HPh), 6.35 (1H, d, J = 8.5 Hz, H-5¢), 6.03 (1H,
dtd, J = 17, 6.8, 3.7 Hz, CHOR), 4.65 (1H, d, J = 12.0 Hz,
CHAPh), 4.55 (1H, d, J = 12.0 Hz, CHBPh), 4.07 (3H, s, CH3),
3.99 (3H, s, CH3), 3.95 (1H, ddd, J = 11.3, 3.8, 1.8 Hz, CHAOBn),
3.87 (1H, dd, J = 11.3, 6.9 Hz, CHBOBn); 13C NMR (100 MHz,
CDCl3): d 166.1 (CO2), 163.7 (C-2¢/C-4¢), 161.9 (C-2¢/C-4¢), 144.1
(C-6¢), 137.3 (CPh), 128.4, 127.8, 127.6 (CHPh), 116.8 (tt, J = 314,
40 Hz, CF2Br), 113.7 (ddt, J = 264, 256, 32 Hz, CF2), 102.9 (C-1¢),
102.1 (C-5¢), 73.2 (CH2Ph), 67.2 (dd, J = 30, 22 Hz, CHOR), 66.5
(2R)-1-(Benzyloxy)-4-bromo-3,3,4,4-tetrafluorobutan-2-yl
benzoate (2R)-6a
Following general procedure A, using benzoyl chloride (0.21 mL,
1.8 mmol) and alcohol (2R)-5 (0.50 g, 1.5 mmol), ester (2R)-6a
was isolated as a colourless oil (0.64 g, 1.5 mmol, 97%.). ee = 89%
(determined on Chiracel OD 10 mm column 250 ¥ 4.6 mm (ID),
1 mL min-1, hexane–iPrOH 98 : 2; RT = 5.21, 5.74 min). [a]D19
=
(CH2OBn), 54.2, 54.0 (OCH3); 19F { H} NMR (376 MHz, CDCl3):
1
+12.1 (c 1, MeOH); IR (neat, cm-1): n 3050, 2957 (C–H), 1733
d -63.8 (2F, dd, J = 7, 4 Hz, CF2Br), -113.4 (1F, dt, J = 274, 3 Hz,
CF2A), -119.3 (1F, dd, J = 274, 4 Hz, CF2B); HRMS (ESI+) Calcd
for C19H18BrF4NO5 [M + Na]+: 518.0197, found 518.0199.
1
=
(C O); H NMR (400 MHz, CDCl3): d 8.14 (2H, dm, J = 8.1 Hz,
H-2¢), 7.65 (1H, tm, J = 7.5 Hz, H-4¢), 7.50 (2H, m, H-3¢), 7.38-
7.27 (5H, m, HPh), 6.13 (1H, dtd, J = 17, 7.0, 3.5 Hz, CHOR),
4.68 (1H, d, J = 12.1 Hz, CHAPh), 4.58 (1H, d, J = 12.1 Hz,
CHBPh), 4.02 (1H, dd, J = 11.1, 3.5, 1.7 Hz, CHAOBn), 3.93 (1H,
dd, J = 11.1, 7.2 Hz, CHBOBn); 13C NMR (100 MHz, CDCl3): d
164.6 (CO2), 137.2 (CPh), 133.8 (C-4¢), 130.2 (C-3¢), 128.6 (C-1¢),
128.6 (CHPh), 128.5 (C-2¢), 127.9 (CHPh), 127.7 (CHPh), 116.8 (tt, J =
313, 39 Hz, CF2Br), 113.6 (ddt, J = 262, 256, 31 Hz, CF2), 73.3
(CH2Ph), 68.1 (dd, J = 30, 22 Hz, CHOR), 66.5 (CH2OBn); 19F
1-(Benzyloxy)-4-bromo-3,3,4,4-tetrafluorobutan-2-yl
2,6-dichloronicotinate ( )-6d
Following general procedure B, using 2,6-dichloropyridine-3-
carboxylic acid (0.32 g, 1.7 mmol) and alcohol ( )-5 (0.50 g,
1.5 mmol), ester ( )-6d was isolated as colourless oil (0.73 g,
-1
=
1.4 mmol, 96%). IR (neat, cm ): n 3047, 2955 (C–H), 1758 (C O);
1H NMR (400 MHz, CDCl3): d 8.12 (1H, d, J = 8.0 Hz, H-6¢), 7.36
(1H, d, J = 8.0 Hz, H-5¢), 7.35-7.27 (5H, m, HPh), 6.05 (1H, dddd,
J = 15, 7.5, 7.5, 3.2 Hz, CHOR), 4.63 (1H, d, J = 12.0 Hz, CHAPh),
4.53 (1H, d, J = 12.0 Hz, CHBPh), 3.96 (1H, ddd, J = 11.1, 3.1,
1
{ H} NMR (376 MHz, CDCl3): d -63.9 (2F, t, J = 4 Hz, CF2Br),
-113.6 (1F, dt, J = 274, 4 Hz, CF2A), -119.0 (1F, dt, J = 274,
4 Hz, CF2B); HRMS (ESI+) Calcd for C18H15BrF4O3 [M + Na]+:
457.0033, found 457.0035.
2.2 Hz, CHAOBn), 3.89 (1H, dd, J = 11.1, 8.0 Hz, CHBOBn); 13
C
NMR (100 MHz, CDCl3): d 161.4 (CO2), 153.8, 150.5 (C-2¢, C-4¢),
142.6 (C-6¢), 136.8 (CPh), 128.5, 128.0, 127.7 (CHPh), 123.6 (C-1¢),
122.9 (C-5¢), 116.5 (tt, J = 313, 39 Hz, CF2Br), 113.2 (ddt, J = 263,
257, 32 Hz, CF2), 73.4 (CH2Ph), 68.7 (dd, J = 30, 22 Hz, CHOR),
(2R)-1-(Benzyloxy)-4-bromo-3,3,4,4-tetrafluorobutan-2-yl
1-naphthoate (2R)-6b
Following general procedure A, using naphthoyl chloride (0.27 ml,
1.8 mmol) and alcohol (2R)-5 (0.50 g, 1.5 mmol), ester (2R)-6b was
66.1 (CH2OBn); 19F { H} NMR (376 MHz, CDCl3): d -64.2 (2F,
1
isolated as a colourless oil (0.65 g, 1.4 mmol, 94%.). [a]1D9 = +15.3
dd, J = 7, 4 Hz, CF2Br), -114.1 (1F, dt, J = 275, 3 Hz, CF2A),
-118.7 (1F, dtd, J = 275, 5, 3 Hz, CF2B); HRMS (ESI+) Calcd for
C17H12BrCl2F4NO3 [M + Na]+: 525.9206, found 525.9208.
-1
=
(c 1, MeOH); IR (neat, cm ): n 3020, 2956 (C–H), 1732 (C O);
1H NMR (400 MHz, CDCl3): d 8.92 (1H, d, J = 8.8 Hz, H-8¢),
8.24 (1H, dd, J = 7.3, 1.2 Hz, H-4¢), 8.08 (1H, d, J = 8.2 Hz,
H-2¢), 7.91 (1H, d, J = 8.0 Hz, H-5¢), 7.63 (1H, ddd, J = 8.5,
6.8, 1.4 Hz, H-6¢/H-7¢), 7.57 (1H, ddd, J = 8.5, 6.8, 1.2 Hz, H-
6¢/H-7¢), 7.53 (1H, dd, J = 8.0, 7.5 Hz, H-3¢), 7.32-7.25 (5H, m,
HPh), 6.19 (1H, dtd, J = 17, 7.3, 3.4 Hz, CHOR), 4.68 (1H, d,
J = 12.0 Hz, CHAPh), 4.57 (1H, d, J = 12.0 Hz, CHBPh), 4.04
(1H, ddd, J = 11.2, 3.3, 2.0 Hz, CHAOBn), 3.96 (1H, dd, J =
1-(Benzyloxy)-4-bromo-3,3,4,4-tetrafluorobutan-2-yl
2,4-difluorobenzoate ( )-6e
Following general procedure A, using 2,4-difluorobenzoic acid
(0.21 ml, 1.8 mmol) and alcohol ( )-5 (0.50 g, 1.5 mmol), ester
( )-6e was isolated as a colourless oil (0.41 g, 0.9 mmol, 57%.).
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IR (neat, cm ): n 3046, 2952 (C–H), 1749 (C O); 1H NMR
(500 MHz, CDCl3): d 8.00 (1H, td, J = 8.4, 6.5 Hz, H-6¢), 7.34-
7.27 (5H, m, HPh), 6.97 (1H, dddd, J = 9.7, 8.5, 2.4, 0.8 Hz, H-5¢),
6.92 (1H, ddd, J = 11.1, 8.5, 2.4 Hz, H-3¢), 6.06 (1H, dddd, J =
16, 7.6, 7.3, 3.3 Hz, CHOR), 4.64 (1H, d, J = 12.1 Hz, CHAPh),
4.55 (1H, d, J = 12.1 Hz, CHBPh), 3.97 (1H, ddd, J = 11.2, 3.1,
by column chromatography (pet. ether 40–60◦/Et2O, 90 : 10). IR
(neat, cm-1): n 3510 (O–H), 3055, 2978(C–H); 1HNMR (400 MHz,
CDCl3): d 7.66 (1.1H, td, J = 8.7, 6.5 Hz, H-6¢major), 7.61 (1H, td,
J = 8.8, 6.4 Hz, H-6¢minor), 7.41-7.30 (10.5H, m, HPh), 6.95-6.89
(2.1H, m, H-3¢), 6.87 (2.1H, ddd, J = 13, 8.7, 2.4 Hz, H-5¢),
5.15 (1.1H, br s, OHmajor), 4.74 (1.1H, dddd, J = 15, 10.5, 6.7,
4.8 Hz, H-5major), 4.68 (2.1H, s, CHAPh), 4.64 (2.1H, s, CHBPh),
4.64-4.58 (1H, m, H-5minor), 3.91-3.85 (2.1H, m, CHAOBn), 3.83
(1H, dd, J = 11.1, 2.9 Hz, CHBOBnminor), 3.78 (1.1H, dd, J =
11.1, 7.0 Hz, CHBOBnmajor), 3.69 (1H, br s, OHminor); 13C NMR
(125 MHz, CDCl3): d 13C Signals could not be assigned as major
or minor product 164.1 (dd, J = 253, 12 Hz, C-2¢/C-4¢), 164.1 (dd,
J = 251, 11 Hz, C-2¢/C-4¢), 160.8 (dd, J = 256, 12 Hz, C-2¢/C-4¢),
160.7 (dd, J = 254, 12 Hz, C-2¢/C-4¢), 137.1 (CPh), 136.0 (CPh),
130.0 (d, J = 4 Hz, C-1¢), 129.9 (d, J = 4 Hz, C-1¢), 128.7, 128.5,
128.4, 128.0, 128.0, 127.8 (CHPh), 120-115 (m, 2 ¥ C-3/C-4), 118.6
(dd, J = 12, 4 Hz, C-6¢), 118.3 (dd, J = 12, 4 Hz, C-6¢), 118-112
(m, 2 ¥ C-3/C-4), 111.3 (dd, J = 22, 4 Hz, C-5¢), 110.9 (dd, J =
21, 4 Hz, C-5¢), 104.8 (t, J = 26 Hz, C-3¢), 104.7 (t, J = 26 Hz,
C-3¢), 100.0 (ddd, J = 31, 23, 2 Hz, C-2), 99.1 (ddd, J = 33, 23,
2 Hz, C-2), 78.6 (ddd, J = 30, 23, 3 Hz, C-5), 77.0 (dmd, J = 30,
2 Hz, overlapping with CDCl3, C-5), 74.2 (CH2Ph), 73.7 (CH2Ph),
66.1 (t, J = 4 Hz, CH2OBn), 60.0 (d, J = 8 Hz, CH2OBn); 19F
-1
=
1.9 Hz, CHAOBn), 3.89 (1H, dd, J = 11.2, 7.6 Hz, CHBOBn); 13
C
NMR (125 MHz, CDCl3): d 166.3 (dd, J = 258, 12 Hz, C-2¢/C4¢),
163.3 (dd, J = 266, 13 Hz, C-2¢/C4¢), 161.2 (d, J = 4 Hz, CO2),
137.1 (CPh), 134.2 (dd, J = 11, 1 Hz, C-1¢), 128.4, 127.9, 127.6
(CHPh), 116.7 (tt, J = 313, 40 Hz, CF2Br), 113.6 (dd, J = 10, 3 Hz,
C-6¢), 113.3 (ddt, J = 263, 257, 31 Hz, CF2), 111.8 (dd, J = 22,
4 Hz, C-5¢), 105.5 (t, J = 26 Hz, C-3¢), 73.3 (CH2Ph), 68.1 (dd, J =
30, 23 Hz, CHOR) 66.3 (CH2OBn); 19F { H} NMR (376 MHz,
1
CDCl3): d -64.0 (2F, s, CF2Br), -99.9 (1F, d, J = 13 Hz, F-2¢/F-
4¢), -102.5 (1F, d, J = 14 Hz, F-2¢/F-4¢), -113.7 (1F, dd, J = 275,
2 Hz, CF2A), -119.0 (1F, dt, J = 275, 4 Hz, CF2B); HRMS (ESI+)
Calcd for C18H13BrF6O3 [M + Na]+: 492.9844, found 492.9849.
5-[(Benzyloxy)methyl]-2-(2,6-dichloropyridin-3-yl)-3,3,4,4-
tetrafluorotetrahydrofuran-2-ol ( )-7d
Following general procedure C, using ester ( )-6d (1.0 g,
2.0 mmol), furanol ( )-7d was isolated as a colourless oil (0.81 g,
1.9 mmol, 97%) in a 1.2 : 1 mixture of anomers after purification by
column chromatography (gradual elution, pet. ether 40–60◦/Et2O,
90 : 10–50 : 50). IR (neat, cm-1): n 3502 (O–H), 3049, 2981 (C–H);
1H NMR (400 MHz, CDCl3): d 8.07 (1.2 H, d, J = 8.2 Hz, H-
4¢major), 8.01 (1H, d, J = 8.2 Hz, H-4¢minor), 7.42-7.33 (11H, m, HPh),
7.32 (1H, d, J = 8.2 Hz, H-5¢minor), 7.32 (1.2H, d, J = 8.2 Hz,
H-5¢major), 5.64 (1.2 H, s, OHmajor), 4.74 (1H, dddd, J = 16, 9.6,
6.4, 4.8 Hz, H-5minor), 4.71 (2.2 H, d, J = 12.3 Hz, CHAPh),
4.64 (2.2 H, d, J = 12.3 Hz, CHBPh), 4.63 (1.2H, dddd, J =
16, 6.5, 6.3, 3.3 Hz, H-5major), 4.09 (1H, s, OHminor), 3.92 (1H,
dd, J = 10.9, 4.7 Hz, CHAOBnminor), 3.87 (1.2H, dd, J = 11.1,
3.6 Hz, CHAOBnmajor), 3.85-3.80 (2.2H, m, CHBOBn); 13C NMR
(100 MHz, CDCl3): d 151.6 (C-2¢/C-6¢minor), 151.1 (C-2¢/C-6¢major),
149.2 (C-2¢/C-6¢major), 149.1 (C-2¢/C-6¢minor), 140.7 (C-4¢minor), 140.5
(C-4¢major), 137.0 (CPhminor ), 135.6 (CPhmajor ), 129.1 (C-3¢major), 128.8,
128.6 (CHPh), 128.6 (C-3¢minor), 128.6, 128.1, 127.8 (CHPh), 122.9
(C-5¢minor), 122.5 (C-5¢major), 122-116 (m, C-3, C-4), 100.4 (t, J =
27 Hz, C-2major), 99.2 (dd, J = 33, 23 Hz, C-2minor), 78.9 (dd,
J = 30, 24 Hz, C-5major), 77.2 (m, overlapping with CDCl3, C-
5minor), 74.4 (CH2Phmajor), 73.8 (CH2Phminor), 66.2 (dd, J = 5, 3 Hz,
1
{ H} NMR (376 MHz, CDCl3): d -106.5 (1.1F, d, J = 9 Hz, F-
2¢/F-4¢major), -107.2 (1F, m, F-2¢/F-4¢minor or major), -107.5 (1F, d, J =
9 Hz, F-2¢/F-4¢minor), -108.5 (1F, ddd, J = 23, 10, 6 Hz, F-2¢/F-
4¢minor or major), -111.5 (1.1F, dm, J = 243 Hz, F-3/F-4Amajor ), -118.7
(1.1F, ddd, J = 246, 11, 6 Hz, F-3/F-4Xmajor ), 121.5 (1.1F, dd, J =
246, 6 Hz, F-3/F-4Ymajor ), -122.3 (1F, ddm, J = 241, 10 Hz, F-
3/F-4Aminor ), -122.9 (1F, dd, J = 238, 4 Hz, F-3/F-4Xminor ), -127.4
(1F, ddt, J = 241, 15, 7 Hz, F-3/F-4Bminor ), -128.4 (1F, ddt, J =
238, 23, 5 Hz, F-3/F-4Yminor ), -132.7 (1.1F, dd, J = 243, 5 Hz,
F-3/F-4Bmajor ); HRMS (ESI+) Calcd for C18H14F6O3 [M + Na]+:
415.0739, found 415.0738.
(2R,5S)-2-[(Benzyloxy)methyl]-3,3,4,4-tetrafluoro-5-
phenyltetrahydrofuran (2R,5S)-8a
Following general procedure D, starting with crude furanol
(2R,5S)-7a (1.3 mmol, obtained from ester (2R)-6a following
general procedure C), benzyl protected C-nucleoside (2R,5S)-8a
was isolated as a colourless oil (0.26 g, 0.76 mmol, 60%) as a 5 : 1
b : a anomeric mixture. ee = 90% (determined on Chiracel OD
10 mm column 250 ¥ 4.6 mm (ID), 1 mL min-1, hexane–iPrOH
99 : 1; RT (major diastereomer) = 19.7, 22.7 min); [a]1D9 = +16.7
CH2OBnmajor), 65.6 (d, J = 8 Hz, CH2OBnminor); 19F { H} NMR
1
1
-113.7 (1F, dt, J = 243, 3 Hz, F-3/F-4Aminor ), -117 (1.2F, dt, J =
245, 4 Hz, F-3/F-4Amajor ), -120.8 (2.4F, t, J = 4 Hz, F-3/F-4major),
-121.1 (1F, ddd, J = 240, 5, 3 Hz, F-3/F-4Xminor ), -121.5 (1.2F,
dt, J = 245, 4 Hz, F-3/F-4Bmajor ), -122.2 (1F, d, J = 240 Hz, F-
3/F-4Yminor ), -134.5 (1F, dd, J = 243, 5 Hz, F-3/F-4Bminor ); HRMS
(ESI+) Calcd for C17H13Cl2F4NO3 [M + Na]+: 448.0101, found
448.0106.
(c 1, MeOH); IR (neat, cm-1): n 3035, 2924 (C–H); H NMR
(400 MHz, CDCl3): d 7.50-7.30 (50H, m, Harom), 5.23 (1H, dd, J =
20, 6.9 Hz, H-5minor), 4.99 (4H, ddd, J = 17, 9.6, 1.3 Hz, H-5major),
4.70 (4H, d, J = 11.9 Hz, CHAPhmajor), 4.69 (1H, d, J = 12.0 Hz,
CHAPhminor), 4.66 (4H, d, J = 11.9 Hz, CHBPhmajor), 4.64 (1H, d,
J = 12.0 Hz, CHBPhminor), 4.63-4.55 (1H, m, H-2minor), 4.45-4.36
(4H, m, H-2major), 3.93 (4H, dd, J = 10.8, 4.8 Hz, CHAOBnmajor),
3.91-3.79 (2H, m, CH2OBnminor), 3.84 (4H, dd, J = 10.8, 6.8 Hz,
CHBOBnmajor); 13C NMR (100 MHz, CDCl3): d 13C signals of the
minor diastereomer were not assigned. 137.3 (CPh), 130.9 (br s, C-
1¢), 129.5, 128.5, 128.4, 128.0, 127.8, 127.3 (CHarom ), 117.9 (dddd,
J = 270, 263, 25, 23 Hz, C-3/C-4), 116.9 (ddt, J = 267, 265, 23 Hz,
C-3/C-4), 81.1 (dd, J = 29, 24 Hz, C-2/C-5), 78.9 (ddd, J = 28, 23,
5-[(Benzyloxy)methyl]-2-(2,4-difluorophenyl)-3,3,4,4-
tetrafluorotetrahydrofuran-2-ol ( )-7e
Following general procedure C, using ester ( )-6e (0.36 g,
0.78 mmol), furanol ( )-7d was isolated as a colourless oil (0.18 g,
0.46 mmol, 60%) as 1.1 : 1 mixture of anomers after purification
2 Hz, C-2/C-5), 73.8 (CH2Ph), 66.4 (d, J = 7 Hz, CH2OBn); 19
F
1450 | Org. Biomol. Chem., 2010, 8, 1445–1454
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1
procedure C), benzyl-protected C-nucleoside ( )-8c was isolated
as an amorphous white solid (0.13 g, 0.31 mmol, 77%) as
a 2 : 1 b : a anomeric mixture. Careful purification by column
chromatography afforded benzyl-protected C-nucleoside ( )-8c
(80 mg, 0.20 mmol, 50%) as a 5 : 1 b : a anomeric mixture. IR
{ H} NMR (376 MHz, CDCl3): d -115.6 (4F, dd, J = 243, 6 Hz,
F-3A
), -122.0 (4F, ddd, J = 238, 6, 3 Hz, F-4Amajor ), -127.5 (1F,
dt, Jm=ajor238, 4 Hz, F-4Aminor ), -127.6 (2F, dd, J = 7, 4 Hz, F-3minor),
-128.0 (4F, d, J = 238 Hz, F-4Bmajor ), -131.0 (1F, dt, J = 238, 7 Hz,
F-4Bminor ), -133.9 (4F, dt, J = 243, 3 Hz, F-3Bmajor ); HRMS (ESI+)
Calcd for C18H16F4O2 [M + H]+: 341.1165, found 341.1170.
1
(neat, cm-1): n 3062, 2962 (C–H); H NMR (400 MHz, CDCl3):
d 7.64 (1H, d, J = 8.1 Hz, H-4¢minor), 7.60 (5H, d, J = 8.1 Hz, H-
4¢major), 7.42-7.28 (29H, m, HPh), 6.38 (1H, d, J = 8.1 Hz, H-5¢minor),
6.38 (5H, d, J = 8.1 Hz, H-5¢major), 5.53 (1H, ddd, J = 18, 7.1,
3.5 Hz, H-2minor), 5.33 (5H, dd, J = 15, 10.4 Hz, H-2major), 4.67 (6H,
d, J = 12.0 Hz, CHAPh), 4.62 (5H, d, J = 12.0 Hz, CHBPhmajor),
4.61 (1H, d, J = 12.0 Hz, CHBPhminor), 4.60-4.50 (1H, m, H-5minor),
4.40-4.27 (5H, m, H-5major), 3.97 (15H, s, OCH3major ), 3.96 (3H, s,
OCH3minor ), 3.94 (18H, s, OCH3), 3.90 (5H, dd, J = 10.8, 4.6 Hz,
CHAOBnmajor), 3.85 (1H, dd, J = 10.8, 5.1 Hz, CHAOBnminor), 3.83-
3.75 (3H, m, CHBOBn); 13C NMR (100 MHz, CDCl3): d 163.7
(C-2¢/C-6¢minor), 163.7 (C-2¢/C-6¢major), 160.3 (C-2¢/C-6¢minor), 160.2
(C-2¢/C-6¢major), 140.3 (C-4¢major), 140.2 (C-4¢minor), 137.9 (CPhmajor ),
137.3 (CPhminor ), 128.5 (CHPhmajor ), 128.5 (CHPhminor ), 127.9 (CHPhmajor ),
127.9 (CHPhminor ), 127.8 (CHPhmajor ), 127.7 (CHPhminor ), 118.5 (dddd,
J = 261, 257, 28, 22 Hz, C-3/C-4minor), 117.8 (ddt, J = 268, 265,
23 Hz, C-3/C-4major), 117.2 (ddt, J = 267, 264, 22 Hz, C-3/C-
4major), 117.2 (dddd, J = 264, 260, 26, 21 Hz, C-3/C-4minor), 104.9
(C-3¢minor), 104.7 (C-3¢major), 101.3 (C-5¢major), 101.3 (C-5¢minor), 78.2
(dd, J = 27, 23 Hz, C-5major), 77.5 (ddd, J = 27, 22, 2 Hz, C-5minor),
75.7 (dd, J = 30, 24 Hz, C-2major), 77.5 (ddd, J = 29, 22, 3 Hz,
C-2minor), 73.8 (CH2Phminor), 73.7 (CH2PHmajor), 66.5 (d, J = 7 Hz,
CH2OBnminor), 66.2 (d, J = 7 Hz, CH2OBnmajor), 53.6, 53.6, 53.5,
(2R,5S)-2-[(Benzyloxy)methyl]-3,3,4,4-tetrafluoro-5-
(1-naphthyl)tetrahydrofuran (2R,5S)-8b
Following general procedure D, starting with crude furanol
(2R,5S)-7b (1.1 mmol, obtained from ester (2R)-6b following
general procedure C), benzyl-protected C-nucleoside (2R,5S)-8a
was isolated as a colourless oil (0.26 g, 0.66 mmol, 63%) in a
4 : 1 b : a anomeric mixture. ee = 89% (determined on Chiracel
10 mm AD column 250 ¥ 4.6 mm (ID), 1 mL min-1, hexane–
iPrOH 99 : 1, RT (major diastereomer) = 11.3 and 23.4 min);
[a]1D9 = +18.6 (c 1, MeOH); IR (neat, cm-1): n 3065, 2910 (C–
1
H); H NMR (400 MHz, CDCl3): d 7.96 (4H, d, J = 8.2 Hz,
H-8¢major), 7.94-7.88 (11H, m, H-4¢, H-5¢, H-8¢minor), 7.77-7.71
(5H, m, H-2¢), 7.66-7.50 (15H, m, H-7¢, H-6¢, H-3¢), 7.44-7.37
(20H, m, HPhmajor ), 7.37 (5H, m, HPhminor ), 6.12 (1H, ddd, J =
18, 6.6, 2.6 Hz, H-5minor), 5.85, (4H, dd, J = 14, 10.8 Hz, H-
5major), 4.76-4.63 (1H, m, H-2minor), 4.73 (4H, d, J = 12.1 Hz,
CHAPhmajor), 4.71 (1H, d, J = 12.1 Hz, CHAPhminor), 4.69 (4H, d,
J = 12.1 Hz, CHBPhmajor), 4.66 (1H, d, J = 12.1 Hz, CHBPhminor),
4.57-4.45 (4H, m, H-2major), 4.01 (4H, dd, J = 10.8, 4.6 Hz,
CHAOBnmajor), 3.96 (1H, dd, J = 10.8, 5.1 Hz, CHAOBnminor),
3.95 (4H, dd, J = 10.8, 6.4 Hz, CHBOBnmajor), 3.91 (1H, dd, J =
10.8, 6.2 Hz, CHBOBnminor); 13C NMR (100 MHz, CDCl3): d 137.3
(CPhmajor ), 137.3 (CPhminor ), 133.5 (C-9¢/C-10¢minor), 133.5 (C-9¢/C-
10¢major), 130.8 (C-9¢/C-10¢minor), 130.7 (C-9¢/C-10¢major), 129.8 (C-
4¢/C-5¢major), 129.7 (C-4¢/C-5¢minor), 129.0 (C-4¢/C-5¢major), 128.9 (C-
4¢/C-5¢minor), 128.5 (CHPhmajor ), 128.5 (CHPhminor ), 128.0(C-3¢/C-6¢/C-
7¢major), 128.0 (C-3¢/C-6¢/C-7¢minor), 127.8 (C-3¢/C-6¢/C-7¢major),
127.8 (C-3¢/C-6¢/C-7¢minor), 127.4 (br s, C-1¢minor), 127.0 (br s, C-
1¢major), 126.8 (C-2¢major), 126.7 (C-2¢minor), 125.9 (CHPhmajor ), 125.9
(CHPhminor ), 125.6 (C-3¢/C-6¢/C-7¢minor), 125.3 (C-3¢/C-6¢/C-7¢major),
122.5 (m, C-8¢minor), 122.5 (d, J = 3.6 Hz, C-8¢major), 117.8 (ddt,
J = 267, 264, 24 Hz, C-3/C-4major), 117.6 (ddt, J = 269, 264,
23 Hz, C-3/C-4major), (C-3/C-4 of the minor diastereomer were
not assigned), 78.6 (dd, J = 28, 24 Hz, C-2/C-5major), 78.5 (dd,
J = 27, 23 Hz, C-2/C-5major), 77.8 (dd, J = 27, 22 Hz, C-2/C-
5minor), 77.8 (dd, J = 27, 23 Hz, C-2/C-5minor), 73.9 (CH2Phminor),
73.8 (CH2Phmajor), 66.7 (d, J = 7 Hz, CH2OBnminor), 66.2 (d, J =
1
53.5 (OCH3); 19F { H} NMR (376 MHz, CDCl3): d -118.6 (2F,
ddd, J = 241, 6, 2 Hz, F-3/F-4Amajor ), -119.9 (2F, ddd, J = 237,
6, 2 Hz, F-3/F-4Xmajor ), -126.2 (1F, ddd, J = 243, 9, 4 Hz, F-3/F-
4Aminor ), 126.9 (1F, dd, J = 237, 9 Hz, F-3/F-4Xminor ), -127.9 (1F,
dd, J = 243, 9 Hz, F-3/F-4Bminor ), -128.4 (2F, dt, J = 237, 2 Hz,
F-3/F-4Ymajor ), -129.7 (1F, ddd, J = 237, 9, 4 Hz, F-3/F-4Yminor ),
-133.8 (2F, dt, J = 241, 2 Hz, F-3/F-4Bmajor ); HRMS (ESI+) Calcd
for C12H13F4NO4 [M + Na]+: 334.0673, found 334.0673.
[(2R,5S)-3,3,4,4-Tetrafluoro-5-phenyltetrahydrofuran-2-
yl]methanol (2R,5S)-9a
Following general procedure E, using benzyl-protected C-
nucleoside (2R,5S)-8a (0.24 g, 0.71 mmol), C-nucleoside (2R,5S)-
9a was isolated as an amorphous white solid (0.16 g, 0.64 mmol,
90%) as a 5 : 1 b : a anomeric mixture. Or:
Following general procedure G, using diastereomerically pure
acetyl-protected C-nucleoside (2R,5S)-11a (38 mg, 0.13 mmol), C-
nucleoside (2R,5S)-9a was isolated as an amorphous white solid
(25 mg, 0.10 mmol, 77%). [a]2D1 = +16.7 (c 1, CHCl3); mp =
48 ◦C; IR (neat, cm-1): n 3545 (O–H), 3054, 2932 (C–H); 1H NMR
(400 MHz, CDCl3): d 7.46-7.39 (5 H, m, HPh), 5.00 (1H, ddd,
J = 17, 8.3, 1.5 Hz, H-5), 4.31 (1H, ddd, J = 20, 12.5, 5.6 Hz,
H-2), 4.06 (1H, dd, J = 12.5, 5.6 Hz, CHAOH), 4.02 (1H, dd, J =
12.5, 6.3 Hz, CHBOH), 1.94 (1H, br s, OH); 13C NMR (100 MHz,
CDCl3): d 130.6 (br s, CPh), 129.6, 128.5, 127.3 (CHPh), 118.1 (dddd,
J = 270, 262, 26, 23 Hz, C-3/C-4), 116.8 (tt, J = 266, 23 Hz, C-
3/C-4), 80.7 (dd, J = 28, 24 Hz, C-5), 79.9 (ddd, J = 28, 23, 3 Hz,
1
7 Hz, CH2OBnmajor); 19F { H} NMR (376 MHz, CDCl3): d -117.8
(4F, ddd, J = 238, 6, 2 Hz, F-3Amajor ), -118.5 (4F, ddd, J = 241, 6,
2 Hz, F-4A
), -124.7 (1F, dd, J = 239, 9 Hz, F-3Aminor ) -125.8
(1F, ddd, Jm=ajor243, 9, 4 Hz, F-4Aminor ), -127.1 (4F, dm, J = 238 Hz,
F-3Bmajor ), -127.3 (1F, ddd, J = 239, 8, 4 Hz, F-3Bminor ), -127.6 (1F,
dd, J = 243, 8 Hz, F-4Bminor ), -133.2 (4F, dm, J = 241 Hz, F-4Bmajor );
HRMS (ESI+) Calcd for C22H18F4O2 [M + H]+: 391.1321, found
391.1324.
3-{5-[(Benzyloxy)methyl]-3,3,4,4-tetrafluorotetrahydrofuran-
2-yl}-2,6-dimethoxypyridine ( )-8c
1
C-2), 59.7 (dd, J = 7, 2 Hz, CH2OH); 19F { H} NMR (376 MHz,
Following general procedure D, starting with crude furanol ( )-
7c (0.41 mmol, obtained from ester ( )-6c following general
CDCl3): d -113.6 (1F, dd, J = 244, 7 Hz, F-3A), -124.1 (1F, ddd,
J = 238, 6, 4 Hz, F-4A), -128.7 (1F, dd, J = 238, 4 Hz, F-4B),
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-134.6 (1F, dt, J = 244, 3 Hz, F-3B); HRMS (ESI+) Calcd for
7.76 (1H, d, J = 7.1 Hz, H-2¢), 7.61-7.52 (3H, m, H-3¢, H-6¢, H-
7¢), 6.12 (1H, ddd, J = 17, 6.8, 2.7 Hz, H-5), 4.76-4.56 (1H, m,
H-2), 4.16-4.05 (2H, m, CH2OH), 1.97 (1H, br s, OH); 13C NMR
(125 MHz, CDCl3): d 133.6, 130.8 (C-9¢/C-10¢), 129.9, 129.0 (C-
4¢/C-5¢), 127.1 (br s, C-1¢), 126.8 (C-3¢/C-6¢/C-7¢), 126.0 (C-2¢),
125.3 (C-3¢/C-6¢/C-7¢), 125.2 (C-3¢/C-6¢/C-7¢), 122.4 (d, J = 4 Hz,
C-8¢), 118.7 (dddd, J = 269, 261, 27, 27 Hz, C-3/C-4), 117.6 (dddd,
J = 270, 266, 27, 24 Hz, C-3/C-4), 78.8 (ddd, J = 26, 22, 2 Hz,
C-5), 76.9 (ddd, J = 27, 21, 2 Hz, C-2), 59.6 (d, J = 8 Hz, CH2OH);
C11H10F4O2 [M + Na]+: 273.0533, found 273.0535.
[(2R,5R)-3,3,4,4-Tetrafluoro-5-phenyltetrahydrofuran-2-
yl]methanol (2R,5R)-9a
Following general procedure G, using diastereomerically pure
acetyl-protected C-nucleoside (2R,5R)-11a (6 mg, 0.02 mmol),
C-nucleoside (2R,5R)-9a was isolated as a colourless oil ◦(5 mg,
0.02 mmol, 96%). [a]2D1 = -17.0 (c 0.1, CHCl3); mp = 53 C; IR
(neat, cm-1): n 3550 (O–H), 3055, 2988(C–H); 1H NMR(400MHz,
CDCl3): d 7.46-7.39 (5 H, m, HPh), 5.22 (1H, ddd, J = 20, 6.9,
3.0 Hz, H-5), 4.53 (1H, dddd, J = 22, 11.3, 5.5, 3.2 Hz, H-2),
4.02 (2H, d, J = 5.5 Hz, CH2OH), 1.88 (1H, br s, OH); 13C NMR
(100 MHz, CDCl3): d 131.1 (d, J = 2 Hz, CPh), 129.5, 128.5, 127.1
(CHPh), 122-116 (m, C-3, C-4), 79.4 (ddd, J = 27, 23, 3 Hz, C-5),
78.4 (ddd, J = 27, 22, 3 Hz, C-2), 59.5 (dd, J = 8, 2 Hz, CH2OH);
1
19F { H} NMR (376 MHz, CDCl3): d -125.1 (dd, J = 239, 10 Hz,
F-4A), -125.5 (ddd, J = 244, 10, 4 Hz, F-3A), -127.3 (ddd, J = 239,
7, 4 Hz, F-4B), -128.1 (dd, J = 244, 8 Hz, F-3B); HRMS (ESI+)
Calcd for C15H12F4O2 [M - Na]+: 323.0671, found 323.0693
[5-(2,6-Dimethoxypyridin-3-yl)-3,3,4,4-
tetrafluorotetrahydrofuran-2-yl]methanol ( )-9c
1
19F { H} NMR (376 MHz, CDCl3): d -126.7 (1F, dd, J = 244, 9,
BBr3 (0.18 ml of a 1 M solution in CH2Cl2, 0.18 mmol) was
added dropwise over 45 min to a solution of benzyl-protected
C-nucleoside ( )-8c (60 mg, 0.15 mmol, 2 : 1 b : a anomeric ratio),
in CH2Cl2 (12 mL) at -78 ◦C. The solution was left to warm
up to room temperature over 16 h, then MeOH was added
and the solvents were removed in vacuo. Purification by column
chromatography afforded C-nucleoside ( )-9c (32 mg, 0.10 mmol,
69%) as an amorphous white solid as a 1.4 : 1 b : a anomeric
mixture. IR (neat, cm-1): n 3570 (OH), 3062, 2962 (C–H); 1H NMR
(400 MHz, CDCl3): d 7.63 (2.4H, m, H-4¢), 6.38 (1H, d, J = 8.2 Hz,
H-5¢minor), 6.37 (1.4H, d, J = 8.2 Hz, H-5¢major), 5.52 (1H, ddd, J =
18, 6.8, 3.1 Hz, H-5minor), 5.33 (1.4H, dd, J = 16, 8.9 Hz, H-5major),
4.53-4.40 (1H, m, H-2minor), 4.30-4.19 (1.4H, m, H-2major), 4.05-
3.98 (3.8H, m, CH2OH), 3.97 (4.2H, s, OCH3major ), 3.96 (3H, s,
OCH3minor ), 3.94 (7.2 H, s, OCH3), 2.18 (1.4H, br s, OHmajor), 1.81
(1H, br s, OHminor); 13C NMR (100 MHz, CDCl3) 13C Signals could
not be assigned as major or minor product, d 163.8, 163.8, 160.4,
160.3 (C-2¢, C-6¢), 140.4, 140.1 (C-4¢), 122-116 (m, C-3, C-4), 104.6,
104.3 (C-3¢), 101.4, 101.4 (C-5¢), 79.3 (ddd, J = 27, 23, 1 Hz, C-2),
78.6 (ddd, J = 27, 22, 3 Hz, C-2), 75.3 (dd, J = 30, 23 Hz, C-5),
74.1 (ddd, J = 29, 22, 3 Hz, C-5), 59.6 (d, J = 7 Hz, CH2OH),
5 Hz, F-3/F-4A), -127.8 (1F, dd, J = 244, 9 Hz, F-3/F-4B), -127.9
(1F, dd, J = 239, 9 Hz, F-3/F-4X), -130.7 (1F, ddd, J = 239, 9,
5 Hz, F-3/F-4Y); HRMS (ESI+) Calcd for C11H10F4O2 [M + Na]+:
273.0509, found 273.0524.
[(2R,5S)-3,3,4,4-Tetrafluoro-5-(1-naphthyl)tetrahydrofuran-2-
yl]methanol (2R,5S)-9b
Following general procedure E, using benzyl-protected C-
nucleoside (2R,5S)-8b (0.24 g, 0.61 mmol), C-nucleoside (2R,5S)-
9b was isolated as an amorphous white solid (0.18 mg, 0.60 mmol,
98%) as a 4 : 1 b : a anomeric mixture. Or:
Following general procedure G, using diastereomerically pure
acetyl-protected C-nucleoside (2R,5S)-11b (0.10 g, 0.29 mmol), C-
nucleoside (2R,5S)-9b was isolated as an amorphous white solid
(85 mg, 0.28 mmol, 97%). [a]1D9 = +26.1 (c 1, CHCl3); mp = 115 ◦C;
IR (neat, cm-1): n 3540 (O–H), 3054, 2933 (C–H); UV (MeOH,
nm): lmax 221, 270, 280, 290; 1H NMR (400 MHz, CDCl3): d 7.99-
7.91 (3H, m, H-4¢, H-5¢, H-8¢), 7.76 (1H, d, J = 7.2 Hz, H-2¢),
7.62-7.52 (3H, m, H-3¢, H-6¢, H-7¢), 5.86 (1H, dd, J = 15, 9.0 Hz,
H-5), 4.50-4.37 (1H, m, H-2), 4.20-4.10 (2H, m, CH2OH), 1.97
(1H, t, J = 6.5 Hz, OH); 13C NMR (125 MHz, CDCl3): d 133.5,
130.7 (C-9¢, C-10¢), 129.9, 129.0 (C-4¢, C-5¢), 126.9 (C-3¢/C-6¢/C-
7¢), 126.7 (br s, C-1¢), 126.0 (C-2¢), 125.6 (C-3¢/C-6¢/C-7¢), 125.1
(C-3¢/C-6¢/C-7¢), 122.4 (d, J = 3 Hz, C-8¢), 118.0 (ddt, J = 268,
264, 24 Hz, C-3/C-4), 117.6 (ddt, J = 269, 265, 23 Hz, C-3/C-4),
79.6 (dd, J = 27, 23 Hz, C-5), 78.1 (dd, J = 28, 25 Hz, C-2), 59.6
1
59.4 (d, J = 9 Hz, CH2OH), 53.6, 53.6, 53.6, 53.5 (CH3); 19F { H}
NMR (376 MHz, CDCl3): d -116.2 (1.4F, dd, J = 243, 6 Hz, F-
3Amajor ), -122.3 (1.4F, ddd, J = 238, 5, 3 Hz, F-4Amajor ), -125.4 (1F,
ddd, J = 244, 10, 4 Hz, F-3Aminor ), -127.3 (1F, dd, J = 238, 10 Hz,
F-4Aminor ), -128.0 (1F, dd, J = 244, 8 Hz, F-3Bminor ), -128.7 (1.4F,
dd, J = 238, 3 Hz, F-4Bmajor ), -129.1 (1F, ddd, J = 238, 8. 4 Hz, F-
4Bminor ), -134.3 (1.4F, dt, J = 243, 3 Hz, F-3Bmajor ); HRMS (ESI+)
Calcd for C12H13F4NO4 [M + Na]+: 334.0673, found 334.0673;
1
(d, J = 7 Hz, CH2OH); 19F { H} NMR (376 MHz, CDCl3): d
-116.4 (ddd, J = 242, 5, 2 Hz, F-3/F-4A), -119.9 (ddd, J = 239,
6, 3 Hz, F-3/F-4X), -127.4 (ddd, J = 239, 3, 2 Hz, F-3/F-4Y),
-133.7 (dt, J = 242, 3 Hz, F-3/F-4B); HRMS (ESI+) Calcd for
C15H12F4O2 [M - Na]+: 323.0671, found 323.0685
2-(2,6-Dichloropyridin-3-yl)-3,3,4,4-tetrafluorotetrahydro-2H-
pyran-2,5-diol ( )-10d
Following general procedure E, using furanol ( )-8d (25 mg,
0.06 mmol), pyrandiol ( )-10d was isolated as an amorphous white
solid (16 mg, 0.05 mmol, 80%) as a 4 : 1 b : a anomeric mixture. IR
[(2R,5R)-3,3,4,4-Tetrafluoro-5-(1-naphthyl)tetrahydrofuran-
2-yl]methanol (2R,5R)-9b
-1
1
=
(neat, cm ): n 3423 (O–H), 2969 (C–H), 1644 (C C); H NMR
(400 MHz, MeOD): d 8.33 (1H, d, J = 8.4 Hz, H-4¢minor), 8.21 (4H,
d, J = 8.3 Hz, H-4¢major), 7.50 (4H, d, J = 8.3 Hz, H-5¢major), 7.49
(1H, d, J = 8.4 Hz, H-5¢minor), 4.56 (1H, ddd, J = 13, 3.5, 1.7 Hz,
H-6Aminor ), 4.22-4.08 (9H, m, H-4, H-6Amajor ), 3.99-3.90 (5H, m,
H-6B); 13C NMR (100 MHz, CD3OD): d 151.8 (C2¢/C-6¢major),
151.6 (C2¢/C-6¢minor), 150.6 (C2¢/C-6¢major), 150.5 (C2¢/C-6¢minor),
Following general procedure G, using diastereomerically pure
acetyl-protected C-nucleoside (2R,5R)-11b (22 mg, 0.06 mmol), C-
nucleoside (2R,5R)-9b was isolated as an amorphous white solid
(16 mg, 0.05 mmol, 83%). [a]1D9 = -23.4 (c 0.5, CHCl3); mp =
◦
1
119 C; IR (neat, cm-1): n 3543 (O–H), 3054, 2987 (C–H); H
NMR (400 MHz, CDCl3): d 7.96-7.90 (3H, m, H-4¢, H-5¢, H-8¢),
1452 | Org. Biomol. Chem., 2010, 8, 1445–1454
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145.2 (C-4¢minor), 144.8 (C-4¢minor), 131.9 (C-3¢minor), 131.7 (C-3¢major),
123.7 (C-5¢major), 123.6 (C-5¢minor), 120-113 (m, C-3major, C-4major), (C-
2, C-3 and C-4 of the minor diastereomer were not assigned), 97.4
(dd, J = 30, 22 Hz, C-2major), 70.1 (dd, J = 32, 20 Hz, C-5minor),
67.7 (t, J = 19 Hz, C-5major), 63.1 (d, J = 6 Hz, C-6minor), 61.2 (d,
(2R,5S)-11a (48 mg, 0.16 mmol, 41%) and (2R,5R)-11a (6 mg,
0.02 mmol, 5%) as amorphous ◦white solids. (2R,5S)-11a: [a]D19
=
-2.5 (c 1.0, CHCl3); mp = 91 C (decomp.); IR (neat, cm-1): n
1
=
3042, 2928 (C–H), 1752 (C O); H NMR (400 MHz, CDCl3): d
7.46-7.37 (5H, m, H-2¢-H-6¢), 5.01 (1H, ddd, J = 17, 9.0, 1.8 Hz,
H-5), 4.57-4.49 (1H, m, H-2), 4.47-4.36 (2H, m, CH2OAc), 2.14
(3H, s, CH3); 13C NMR (125 MHz, CDCl3): d 170.3 (CO2), 130.5
(C-1¢), 129.7, 128.5, 127.3 (C-2¢-C-6¢), 117.8 (dddd, J = 271, 263,
26, 23 Hz, C-3/C-4), 116.6 (tt, J = 265, 23 Hz, C-3/C-4), 80.9 (dd,
J = 29, 24 Hz, C-5), 77.4 (ddd, J = 29, 23, 2 Hz, C-2), 60.2 (dd,
1
J = 7 Hz, C-6major); 19F { H} NMR (376 MHz, CD3OD): d -117.4
(1F, ddd, J = 267, 15, 10 Hz, F-3/F-4Aminor ), -117.5 (1F, ddd, J =
264, 15, 10 Hz, F-3/F-4Xminor ), -119.8 (4F, ddd, J = 264, 17, 11 Hz,
F-3/F-4Amajor ), -129.6 (4F, ddd, J = 251, 17, 10 Hz, F-3/F-4Xmajor ),
-129.7 (1F, ddd, J = 267, 18, 12 Hz, F-3/F-4Bminor ), -132.3 (4F,
ddd, J = 251, 15, 11 Hz, F-3/F-4Ymajor ), -132.7 (1F, ddd, J = 264,
15, 12 Hz, F-3/F-4Yminor ), -134.1 (4F, ddd, J = 264, 15, 10 Hz, F-
3/F-4Bmajor ); HRMS (ESI-) Calcd for C10H7Cl2F4NO3 [M - H]-:
333.9666, found 333.9666.
1
J = 7, 2 Hz, CH2OAc), 20.6 (CH3); 19F { H} NMR (376 MHz,
CDCl3): d -114.7 (dd, J = 244, 7 Hz, F-3A), -123.4 (ddd, J = 239,
7, 4 Hz, F-4A), -128.4 (dd, J = 239, 4 Hz, F-4B), -133.0 (dt, J =
244, 4 Hz, F-3B); HRMS (ESI+) Calcd for C13H12F4O3 [M + Na]+:
315.0615, found 315.0629.
(2R,5R)-11a. [a]D19 = -6.6 (c 0.5, CHCl3); mp = 94 ◦C
2-(2,4-Difluorophenyl)-3,3,4,4-tetrafluorotetrahydro-2H-pyran-
2,5-diol ( )-10e
-1
1
=
(decomp.); IR (neat, cm ): n 3053, 2927 (C–H), 1751 (C O); H
NMR (400 MHz, CDCl3): d 7.46-7.38 (5H, m, H-2¢-H-6¢), 5.22
(1H, dd, J = 20, 7.5 Hz, H-5), 4.71-4.59 (1H, m, H-2), 4.48 (1H,
dd, J = 12.1, 6.9 Hz, CHAOAc), 4.40 (1H, dd, J = 12.1, 5.5 Hz,
CHBOAc), 2.14 (3H, s, CH3); 13C NMR (125 MHz, CDCl3): d
170.3 (CO2), 130.5 (d, J = 2 Hz, C-1¢), 129.6, 128.6, 127.1 (C-2¢-
C-6¢), 118.3 (tdd, J = 266, 27, 22 Hz, C-3/C-4), 116.6 (ddt, J = 268,
261, 24 Hz, C-3/C-4), 79.5 (dd, J = 27, 23 Hz, C-5), 76.2 (td, J =
Following general procedure E, using furanol ( )-8e (33 mg,
0.08 mmol), pyrandiol ( )-10e was isolated as an amorphous white
solid (19 mg, 0.06 mmol 74%) as a 5 : 1 b : a anomeric mixture. IR
(cm-1): 3424 (O–H), 2960 (C–H); 1H NMR (400 MHz, CD3OD):
d 7.83 (1H, dt, J = 8.9, 6.9 Hz, H-6¢minor), 7.76 (5H, dt, J = 8.8,
6.7 Hz, H-6¢major), 7.03-6.94 (12H, m, H-3¢, H-5¢), 4.56 (1H, ddd,
J = 13, 3.6, 2.0 Hz, H-6Aminor ), 4.22-4.06 (11H, m, H-5, H-6A
),
3.94 (1H, dd, J = 13, 6.1 Hz, H-6Bminor ), 3.89, (5H, dd, J = m1a0jo.r2,
5.2 Hz, H-6Bmajor ); 13C NMR (100 MHz, CD3OD): d 165.3 (dd,
J = 249, 12 Hz, C-2¢/C-4¢major), 165.2 (dd, J = 250, 11 Hz, C-2¢/C-
4¢minor), 162.7 (dd, J = 257, 12 Hz, C-2¢/C-4¢major), 162.7 (dd, J =
257, 12 Hz, C-2¢/C-4¢minor), 133.6 (dd, J = 10, 4 Hz, C-1¢minor), 133.3
(dd, J = 10, 4 Hz, C-1¢major), 121.7 (dm, J = 13 Hz, C-6¢minor), 121.5
(dm, J = 11 Hz, C-6¢major), 116.3 (dddd, J = 260, 254, 31, 20 Hz,
C-3/C-4), 113.2 (dddd, J = 254, 245, 28, 21 Hz, C-3/C-4), (C-3
and C-4 of the minor diastereomer were not assigned), 111.5 (dd,
J = 21, 4 Hz, C-5¢major), 111.4 (dd, J = 21, 4 Hz, C-5¢minor), 105.6
(dd, J = 28, 26 Hz, C-3¢major), 105.4 (dd, J = 27, 26 Hz, C-3¢minor),
97.8-97.2 (m, C-2major), (C-2 of the minor diastereomer were not
assigned), 70.3 (dd, J = 32, 20 Hz, C-5minor), 67.8 (t, J = 20 Hz,
C-5major), 62.8 (d, J = 6 Hz, C-6minor), 61.0 (d, J = 7 Hz, C-6minor);
1
25, 3 Hz, C-2), 60.0 (t, J = 5 Hz, CH2OAc), 20.6 (CH3); 19F { H}
NMR (376 MHz, CDCl3): d -127.4 (2F, br s, F-3), -127.7 (ddd,
J = 239, 8, 4 Hz, F-4A), -130.7 (dm, J = 239 Hz, F-4B); HRMS
(ESI+) Calcd for C13H12F4O3 [M + Na]+: 315.0615, found 315.0634
[(2R,5S)-3,3,4,4-Tetrafluoro-5-(1-naphthyl)tetrahydrofuran-2-
yl]methyl acetate (2R,5S)-11b and [(2R,5R)-3,3,4,4-tetrafluoro-5-
(1-naphthyl)tetrahydrofuran-2-yl]methyl acetate (2R,5R)-11b
Following general procedure F using C-nucleoside (2R,5S)-
9b (0.18 g, 0.60 mmol), afforded acetyl-protected C-nucleoside
(2R,5S)-11b as an amorphous white solid (0.20 g, 0.36 mmol, 97%)
as a 4 : 1 b : a anomeric mixture. Careful column chromatography
afforded (2R,5S)-11b (0.18 g, 0.53 mmol, 88%) and (2R,5R)-11b
(6 mg, 0.02 mmol, 5%) as amorphou◦s white solids. (2R,5S)-11b:
1
19F { H} NMR (376 MHz, CD3OD): d -106.1 (5F, ddd, J = 22,
[a]1D9 = +21.5 (c 1, CHCl3); mp = 78 C; IR (neat, cm-1): n 3054,
11, 10 Hz, F-2¢/F-4¢major), -106.6 (1F, ddd, J = 28, 9, 7 Hz, F-
2¢/F-4¢minor), -110.8 (5F, d, J = 10 Hz, F-2¢/F-4¢major), -111.0 (1F,
d, J = 9 Hz, F-2¢/F-4¢minor), -117.4 (1F, ddd, J = 266, 14, 10 Hz, F-
3/F-4Aminor ), -118.2 (1F, dddd, J = 264, 18, 9, 7 Hz, F-3/F-4Xminor ),
-120.7 (5F, ddt, J = 264, 17, 11 Hz, F-3/F-4Amajor ), -129.6 (5F, J =
251, 18, 11 Hz, F-3/F-4Xmajor ), -129.6 (1F, ddd, J = 266, 18, 11 Hz,
F-3/F-4Bminor ), -132.4 (5F, ddd, J = 251, 15, 10 Hz, F-3/F-4Ymajor ),
-135.3 (1F, dddd, J = 264, 27, 14, 11 Hz, F-3/F-4Yminor ), -136.2
(5F, dddd, J = 264, 23, 15, 10 Hz, F-3/F-4Bmajor ); HRMS (ESI-)
Calcd for C11H8F6O3 [M - H]-: 301.0305, found 301.0304.
1
=
2933 (C–H), 1751 (C O); H NMR (500 MHz, CDCl3): d 7.98-
7.91 (3H, m, H-4¢, H-5¢, H-8¢), 7.75 (1H, d, J = 7.3 Hz, H-2¢),
7.62-7.52 (3H, m, H-3¢, H-6¢, H-7¢), 5.88 (1H, dd, J = 15, 9.7 Hz,
H-5), 4.65-4.48 (3H, m, H-2, CH2OAc), 2.17 (3H, s, CH3); 13C
NMR (125 MHz, CDCl3): d 170.4 (CO2), 133.5, 130.7 (C-9¢, C-
10¢), 129.9, 129.0 (C-4¢, C-5¢), 126.9 (C-3¢/C-6¢/C-7¢), 126.6 (br s,
C-1¢), 125.9 (C-2¢), 125.6, 125.2 (C-3¢/C-6¢/C-7¢), 122.4 (d, J =
3 Hz, C-8¢), 117.7 (ddt, J = 269, 265, 24 Hz, C-3/C-4), 117.4 (ddt,
J = 269, 264, 23 Hz, C-3/C-4), 78.4 (dd, J = 29, 26 Hz, C-5), 77.0
(m, C-2, overlap with CHCl3 signal), 60.1 (d, J = 7 Hz, CH2OAc),
1
20.6 (CH3); 19F { H} NMR (376 MHz, CDCl3): d -117.6 (ddd,
[(2R,5S)-3,3,4,4-Tetrafluoro-5-phenyltetrahydrofuran-2-yl]methyl
acetate (2R,5S)-11a and [(2R,5R)-3,3,4,4-tetrafluoro-5-
phenyltetrahydrofuran-2-yl]methyl acetate (2R,5R)-11a
J = 242, 6, 2 Hz, F-3/F-4A), -118.9 (ddd, J = 239, 6, 2 Hz, F-
3/F-4X), -127.3 (ddd, J = 239, 4, 2 Hz, F-3/F-4Y), -133.0 (ddd,
J = 242, 5, 2 Hz, F-3/F-4B); HRMS (ESI+) Calcd for C17H14F4O3
[M + Na]+: 365.0771, found 365.0767
Following general procedure F, using C-nucleoside (2R,5S)-9a
(0.10 g, 0.40 mmol), acetyl-protected C-nucleoside was isolated
as an amorphous white solid (0.10 g, 0.36 mmol, 89%) as a 5 : 1
b : a anomeric mixture. Careful column chromatography afforded
(2R,5R)-11b. [a]D19 = -15.8 (c 1, CHCl3); mp = 84 ◦C;
-1
1
=
IR (neat, cm ): n 3054, 2933 (C–H), 1751 (C O); H NMR
(400 MHz, CDCl3): d 7.95-7.90 (3H, m, H-4¢, H-5¢, H-8¢), 7.74
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(1H, d, J = 7.3 Hz, H-2¢), 7.62-7.52 (3H, m, H-3¢, H-6¢, H-7¢),
6.11 (1H, ddd, J = 17, 3.2, 2.8 Hz, H-5), 4.77 (1H, ddddd, J =
15, 9.7, 6.8, 5.4, 3.1 Hz, H-2) 4.59 (1H, dd, J = 12.2, 6.8 Hz,
CHAOAc), 4.48 (1H, dd, J = 12.2, 5.4 Hz, CHBOAc), 2.17 (3H, s,
CH3); 13C NMR (125 MHz, CDCl3): d 170.4 (CO2), 133.5, 130.8
(C-9¢, C-10¢), 129.9, 129.0 (C-4¢, C-5¢), 127.0 (br s, C-1¢), 126.9 (C-
3¢/C-6¢/C-7¢), 126.0 (C-2¢), 125.2, 125.2 (C-3¢/C-6¢/C-7¢), 122.4
(d, J = 3 Hz, C-8¢), 118.3 (dddd, J = 269, 261, 26, 22 Hz, C-3/C-
4), 117.4 (dddd, J = 268, 263, 25, 21 Hz, C-3/C-4), 77.0 (ddd, J =
31, 24, 2 Hz, C-2, overlap with CHCl3 signal), 76.2 (ddd, J = 28,
Acknowledgements
We thank the BBSRC, the Cancer Research UK for generous
funding and the Berrow Foundation for a Scholarship to GTG. We
also wish to acknowledge Dr Bruno Linclau (School of Chemistry,
University of Southampton) for insightful discussions.
References
1 L. B. Townsend, in Chemistry of Nucleosides and Nucleotides, Plenum
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1
22, 3 Hz, C-5), 60.0 (d, J = 8 Hz, CH2OAc), 20.7 (CH3); 19F { H}
2 (a) D. Loakes, Nucleic Acids Res., 2001, 29, 2437; (b) A. T. Krueger and
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NMR (376 MHz, CDCl3): d -125.0 (dd, J = 239, 10 Hz, F-4A),
-125.9 (ddd, J = 243, 10, 4 Hz, F-3A), -126.9 (ddd, J = 239, 8,
4 Hz, F-4B), -128.0 (dd, J = 243, 8 Hz, F-3B); HRMS (ESI+)
Calcd for C17H14F4O3 [M + Na]+: 365.0771, found 365.0775
(2R,5S)-[3,3,4,4-Tetrafluoro-5-(1-naphthyl)tetrahydrofuran-2-
yl]methyl triphosphate triethylamine salt (2R,5S)-12b
3 (a) R. W. Miles, P. C. Tyler, R. H. Furneaux, C. K. Bagdassarian and
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5 For recent contributions, see: (a) S. C. Wilkinson, O. Lozano, M.
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Thompson and V. Gouverneur, Tetrahedron: Asymmetry, 2009, 20, 910;
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A. A. Anderson, E. S. Child, D. J. Mann and V. Gouverneur, Bioorg.
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Prior to the reaction, all solids used were dried over P2O5
overnight, and all solvents and amines were dried over molecular
R
sieves overnight. Proton spongeꢀ (1 mg, 5 mmol, 0.08 eq.) and
phosphorous oxychloride (freshly distilled, 6.7 ml, 0.07 mmol,
1.1 eq.) were added to a solution of C-nucleoside (2R,5S)-9b
◦
(20 mg, 0.07 mmol, 1 eq.) in THF (2 mL) at 0 C. The reaction
mixture was stirred for 2 h at 0 ◦C and then for 20 h at room
temperature. A solution of tributylammonium pyrophosphate
(150 mg, 0.27 mmol, 4 eq.) and tributylamine (150 mg, 0.53 mmol,
8 eq.) was added and the reaction was stirred for further 16 h.
TEAB (10 mL of a 0.1 M aqueous solution) was added and
the reaction was stirred for another 24 h. The reaction mixture
was then washed with EtOAc (10 mL) and the aqueous layer
was concentrated in vacuo at room temperature. The crude oil
was redissolved in TEAB (3 mL of a 0.1 M aqueous solution)
and purified by reverse phase HPLC (TEAB (0.1 M, aq.)/MeCN
(100%): t = 0 min, 1% MeCN, t = 5 min, 1% MeCN, t = 15 min,
5% MeCN, t = 45 min, 100% MeCN; RT = 30 min) to afford
C-nucleotide (2R, 5S)-13b (33 mg, 35 mmol, 60%) as a white foam
7 (a) H. W. Kim, P. Rossi, R. K. Schoemaker and S. G. DiMagno, J. Am.
Chem. Soc., 1998, 120, 9082; (b) J. C. Biffinger, H. W. Kim and S. G.
DiMagno, ChemBioChem, 2004, 5, 622.
8 (a) A. J. Boydell, V. Vinader and B. Linclau, Angew. Chem., Int. Ed.,
2004, 43, 5677; (b) R. S. Timofte and B. Linclau, Org. Lett., 2008,
10, 3673; (c) B. Linclau, A. J. Boydell, R. S. Timofte, K. J. Brown, V.
Vinader and A. C. Weymouth-Wilson, Org. Biomol. Chem., 2009, 7,
803.
1
after freeze drying. UV (H2O, nm): lmax 221, 270, 281, 291; H
NMR (400 MHz, D2O): d 8.22 (1H, dd, J = 8.0, 2.5 Hz, H-8¢),
7.93 (2H, br d, J = 8.4 Hz, H-4¢, H-5¢), 7.77 (1H, dd, J = 6.9,
2.0 Hz, H-2¢), 7.60-7.49 (3H, m, H-3¢, H-6¢, H-7¢), 6.11 (1H, dd,
J = 15, 9.8 Hz, H-5), 4.79-4.70 (1H, m, H-2 overlap with D2O
signal), 4.50-4.40 (1H, m, CHAOP), 4.39-4.30 (1H, m, CHBOP),
3.05 (24H, d, J = 7.2 Hz, NCH2CH3), 1.14 (39H, t, J = 7.2 Hz,
NCH2CH3); 13C NMR (125 MHz, D2O): d 133.3 (C-9¢/C-10¢),
130.3 (d, J = 2 Hz, C-9¢/C-10¢), 128.9, 127.2 (C-4¢, C-5¢), 126.8
(C-3¢/C-6¢/C-7¢), 126.4 (d, J = 6 Hz, C-1¢), 126.1 (C-3¢/C-6¢/C-
7¢), 126.1 (d, J = 7 Hz, C-2¢), 125.6 (d, J = 4 Hz, C-3¢/C-6¢/C-7¢),
122.7 (br s, C-8¢), 120-115 (m, C-3, C-4), 78.8-77.4 (m, C-2, C-
9 Q. Wu and C. Simons, Synthesis, 2004, 1533.
10 Two examples of esterification of (2R)-5 with Ac2O and BnOCH2COCl,
and subsequent cyclization were recently reported by Linclau et al. for
ketose formations (ref. 8c).
11 For Lewis acid-promoted reductive dehydroxylation of non-fluorinated
C-nucleosides, see: (a) J. A. Piccirilli, T. Krauch, L. J. MacPherson and
S. A. Benner, Helv. Chim. Acta, 1991, 74, 397; (b) W. Liu, D. S. Wise
and L. B. Townsend, J. Org. Chem., 2001, 66, 4783; (c) S. Hildbrand,
A. Blaser, S. P. Parel and C. J. Leumann, J. Am. Chem. Soc., 1997, 119,
5499; (d) C. Brotschi, A. Ha¨berli and C. J. Leumann, Angew. Chem.,
2003, 115, 1694; C. Brotschi, A. Ha¨berli and C. J. Leumann, Angew.
Chem., Int. Ed., 2001, 40, 3012.
1
5), 62.1 (br s, CH2OP), 46.3 (NCH2), 8.4 (NCH2CH3); 19F { H}
NMR (376 MHz, D2O): d -118.0 (dd, J = 242, 30 Hz, F-3/F-
4A), -119.0 (dd, J = 237, 32 Hz, F-3/F-4X), -126.8 (dd, J =
237, 20 Hz, F-3/F-4Y), -132.8 (dd, J = 242, 24 Hz, F-3/F-4B);
12 Table 3 (entries 1–3) shows the structure of the major diastereomer
only; entry 1: 8a d.r.: 5 : 1, 9a d.r.: 5 : 1; entry 2: 8b d.r.: 4 : 1, 9b d.r.:
4 : 1; entry 3: 8c d.r.: 2 : 1, 9c d.r.: 1.4 : 1. For entries 4 and 5, 10d and
10e were formed as a mixture of diastereomers (d.r. = 4 : 1 for 10d and
d.r. = 5 : 1 for 10e).
1
31P { H} NMR (200 MHz, D2O): d -9.4 (d, J = 20 Hz, g-P),
-10.2--10.7 (m, a-P), -22.0 (br s, b-P); MS (ESI) 538.93 [M - H]-
(100%), 549.00 [M - H2PO3]- (75%), 379.04 [M - H3P2O6]- (65%);
HRMS (ESI-) Calcd for C15H14F4O11P3 [M - H]-: 538.9691, found
538.9693.
13 X. Zhang, H. Xia, X. Dong, J. Jin, W.-D. Meng and F.-L. Qing, J. Org.
Chem., 2003, 68, 9026.
1454 | Org. Biomol. Chem., 2010, 8, 1445–1454
This journal is
The Royal Society of Chemistry 2010
©