2,2′-Bipyridine-3,3′-dicarboxylic carbohydrate esters and amides. Synthesis and preliminary evaluation as ligands in Cu(II)-catalysed enantioselective electrophilic fluorination

Article abstract of DOI:10.1016/j.tetasy.2009.02.050

A series of 10 new carbohydrate-substituted bipyridines were prepared from 2,2′-bipyridine-3,3′-dicarboxylic acid, itself easily available from ortho-phenanthroline. As a preliminary exploration of their use as chiral ligands, Cu(II)-catalysed asymmetric electrophilic fluorination of model β-ketoesters using these simple and easily accessible chiral bipyridines was studied. Only modest enantioselectivity was observed in this reaction, although the ee was in a similar range as those provided by known and more elaborate ligands.

Full text of DOI:10.1016/j.tetasy.2009.02.050

Tetrahedron: Asymmetry 20 (2009) 593–601
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
2,20-Bipyridine-3,30-dicarboxylic carbohydrate esters and amides. Synthesis
and preliminary evaluation as ligands in Cu(II)-catalysed enantioselective
electrophilic fluorination
Aurélie Assalit a,b,c, Thierry Billard a,b, , Stéphane Chambert a,c, Bernard R. Langlois a,b, Yves Queneau a,c,
,
*
*
Diane Coe d
a ICBMS, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires, CNRS, UMR5246, Université de Lyon, Université Lyon 1, INSA-Lyon, CPE Lyon,
43 boulevard du 11 novembre 1918, Villeurbanne F-69622, France
b Laboratoire SERCOF, Université Lyon 1, Bât. Chevreul, France
c Laboratoire de Chimie Organique, INSA Lyon, Bât. Jules Verne, France
d Respiratory CEDD, Medicines Research Centre, GlaxoSmithKline, Gunnels Wood Road, Stevenage SG1 2NY, United Kingdom
a r t i c l e i n f o
a b s t r a c t
A series of 10 new carbohydrate-substituted bipyridines were prepared from 2,20-bipyridine-3,30-dicar-
boxylic acid, itself easily available from ortho-phenanthroline. As a preliminary exploration of their use
as chiral ligands, Cu(II)-catalysed asymmetric electrophilic fluorination of model b-ketoesters using these
simple and easily accessible chiral bipyridines was studied. Only modest enantioselectivity was observed
in this reaction, although the ee was in a similar range as those provided by known and more elaborate
ligands.
Article history:
Received 12 January 2009
Accepted 23 February 2009
Available online 23 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
of their uses as chiral ligands in the copper(II)-catalysed asymmet-
ric electrophilic fluorination.
Carbohydrates are an inexpensive and natural source of chiral-
ity, which have demonstrated their efficiency in chirality control
for a long time, either as chiral appendages inducing diastereofacial
selectivity, as organocatalysts, or as chiral ligands in metallic com-
plexes.1 Among ligands, bipyridines are important systems due to
their ability to efficiently complex metals by multifold bonding,
notably for Cu cations.2 However, only very few examples of carbo-
hydrate bipyridinic systems have been reported in the literature
(Scheme 1). These compounds were designed for bringing sugars
close to metallic centres in Fe, Cu, Re, Tc, or Zn complexes, for appli-
cations towards molecular recognition (sugar–protein interac-
tions),3 asymmetric catalysis,4 or fluorescence by radiolabelled
systems.5 Cyclodextrin bipyridine hybrids were also reported.6
Surprisingly, the readily available synthon 2,20-bipyridine-3,30-
dicarboxylic acid 6, which is commercially available or can be
obtained in one step by simple permanganate oxidation of ortho-
phenanthroline,7 has never been used for preparing carbohy-
drate-substituted bipyridinic systems.
2. Synthesis of bipyridine sugar diesters
The easily available 1,2,5,6-di-O-isopropylidene-a-D-glucofura-
nose (also referred to as diacetone glucose or DAG) was used as
the first substrate. The ability of the bipyridine diacid 6 to provide
the corresponding diester 7 proved to be rather low, either by reac-
tion with the acid chloride derived from 6 or by direct coupling
using EDCI/DMAP (Scheme 2).8 Both the alcohol function in DAG
and the carboxylic acids in 6 suffer from steric hindrance, explain-
ing the moderate reactivity. Ester formation in 7 was confirmed by
the characteristic CO band in the IR spectrum of diester 7
(m
(C@O) = 1732 cmꢀ1) and the typical shift downfield (+0.9 ppm)
of H-3 (d = 5.27 ppm) in the 1H NMR spectrum compared to DAG.
The EDCI/DMAP system, slightly more efficient and simpler to be
set up, was then used for preparing the four other carbohydrate
diesters 8–11 (Scheme 2). With the goal of having a change only
at the chiral centre where the sugar and the bipyridine are con-
The purpose of the present paper is to describe the synthesis of
a series of new monosaccharidic esters and amides of 2,20-bipyri-
dine-3,30-dicarboxylic acid and to report a preliminary evaluation
nected, 1,2,5,6-di-O-isopropylidene-a-D-allofuranose, the epimer
at C-3 of DAG, was used. The corresponding diester 8 was obtained
in a significantly better yield (50%) than 7, revealing an easier
access to OH-3 in the allo substrate more likely to adopt a pseu-
do-equatorial position. Indeed, in the 1H NMR spectrum of the
allose derivative, the coupling constant between H-3 and H-4
(J3,4 = 8.8 Hz) reflects a relationship close to a trans diaxial one,
* Corresponding authors.
E-mail addresses: thierry.billard@univ-lyon1.fr (T. Billard), yves.queneau@
insa-lyon.fr (Y. Queneau).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.02.050

594
A. Assalit et al. / Tetrahedron: Asymmetry 20 (2009) 593–601
OH
OH
HO
OH
O
OH
O
O
AcHN
O
HN
NH
O
O
AcHN
O
5
5
O
OH
N
H
N
H
N
N
1
RO
S
OR
RO
OR
HO
HO
RO
N
RO
O
S
O
OR
O
RO
HO
O
N
N
R = Ac
R = H
NHCOCH3
2
N
3
R
O
R
O
O
N
N
O
R
O
O
O
O
O
R
n
O
O
n
OH
HO
AcO
OAc
AcO
OAc
O
AcO
O
OAc
R
N
N
O
O
O
R = CH3
R
R
R,R = -(CH2)5 -
R
5
n=0,1
4
CO2H
N
KMnO4 / NaOH
H2O reflux
70%
N
CO2H
N
N
ref. 7
6
Scheme 1. Bipyridine carbohydrate systems.
allowing both substituents to stay in pseudo-equatorial positions,
exactly as in the starting alcohol.9 In contrast, for the glucose
system (J3,4 = 2.8 Hz) both substituents have to accommodate a
cis relationship, making the reaction slower. The other diesters
9–11, connected at primary positions of sugars, were prepared di-
rectly from fructose, ribose or partially protected galactose deriva-
tives. Though not optimised, the moderate yields are largely
balanced by the cheapness and the availability of the starting
materials. Moreover, unreacted sugar substrates were easily recov-
ered at the purification stage.
cedure was applied to a glucosamine derivative, namely 1,3,4,6-
tetra-O-acetyl-2-deoxy-2-amino-b- -glucopyranose, leading to
D
diamide 14 in 24% yield. The formation of the amide linkage was
confirmed by the observation of H-3–NH couplings in the proton
NMR spectra for gluco- and allofuranose derivatives 12 and 13
(J = 7.7 Hz and 9.2 Hz, respectively), and of H-2–NH coupling
(J = 8.8 Hz) for the glucosamine-based amide 14.
Two more diamides, substituted on primary position C-1 of
fructose 15 and C-6 of galactose 16, analogous to esters 9 and 11,
were then prepared. In this case, the shorter route, which directly
converts the primary azidodeoxy substrate to the corresponding
amide under Staudinger-Vilarrasa conditions,10 led to the desired
diamides in 21% and 26% yields, respectively. Trials for applying
the latter method towards secondary systems 12–14 proved to
be significantly less efficient than the amine-acid coupling using
the HOBt/EDCI system.
3. Synthesis of bipyridine sugar diamides
We then turned to the synthesis of amides in order to prepare
bipyridine-carbohydrate hybrids with increased chemical stability
than esters (Scheme 3). In the case of secondary amines (deoxya-
minosugars obtained from the corresponding azidodeoxy sugars
by hydrogenation), the diamides were prepared by coupling with
diacid 6 using the HOBt/EDCI system. Chiral diamides 12 and 13,
derived from glucofuranose and allofuranose, and having a carbo-
hydrate backbone that is exactly the same as that in diesters 7 and
8, were obtained in 47% and 30% yields, respectively. The same pro-
4. Evaluation of the new bipyridine-carbohydrate hybrids as
chiral ligands
The new bipyridine-carbohydrate diesters and diamides were
then used in a preliminary investigation of their ability to complex

A. Assalit et al. / Tetrahedron: Asymmetry 20 (2009) 593–601
595
O
O
O
O
O
O
N
HO2C
N
CO2H
N
O
EDCI (4 eq.)
O
O
DMAP (4 eq.)
CH2Cl2
O
N
O
O
HO
O
O
6 (1 eq.)
DAG
O
7
O
(3eq.)
(25%)
O
O
O
OMe
N
O
O
O
O
O
O
O
O
O
O
O
2
O
O
O
O
O
O
N
O
O
O
O
O
O
O
O
N
2
O
2
N
2
10
9
11
(46%)
8
(26%)
(36%)
(50%)
Scheme 2. Bipyridine sugar diesters 7–11.
metallic species within the context of electrophilic fluorination.
This reaction has become a classical tool in the optimisation process
of bioactive compounds,11 since it often increases the metabolic
resistance12 and the lipophilicity13 of the molecules, thus contribut-
ing to the improvement of pharmacokinetic properties of potential
lead drugs.14 Indeed, due to the high electronegativity and the spe-
cific properties of the fluorine atom and the specific physico-chem-
ical properties of fluorinated organic compounds in a wide range of
applications (fluoropolymers, pharmaceutical and agrochemical
products, material science, etc.), organofluorine chemistry has
attracted considerable interest.13–17 One of the methods for intro-
ducing a fluorine atom is the use of reagents that behave as ‘F+’ spe-
cies,18 and since the pioneering work of Differding et al. 20 years
ago,19 various stereoselective versions of this reaction have been re-
ported.11c,20 Indeed, chirality in drugs can originate from stereogen-
ic centres bearing fluorine atoms, as, for example, in Fluticasone, or
Flindokalner (post-stroke neuroprotection)21,22 and in GSK-23A
(hypoglycemia agents),23 two compounds under development.
Two approaches can be distinguished, one based on the use of chiral
fluorinating agents,19,24 and the second involving chiral catalysts
(metal catalysis or organocatalysis), associated with achiral and
commercially available electrophilic fluorinating reagents.16,25–27
Only one report of bipyridine/Cu-mediated enantioselective C–F
bond formation has yet been published by Shibata et al. who used
DNA as a chiral ligand.28 In keeping with catalysis with bipyridine
complexes of copper(II), we studied the Cu(II)-mediated asymmet-
ric fluorination of some b-keto esters in the presence of our new
bipyridinic systems.
in the case of the simpler methyl diester 177 (prepared using the
method that is same as that used for the sugar ones), and two
b-ketoesters, a linear one 18 and a cyclic one 19 (Scheme 4). Two
other fluorinating agents were also used, namely 1-chloromethyl-
4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate),
also called ‘SelectfluorÒ’, and N,N0-difluoro-2,20-bipyridinium bis-
(tetrafluoroborate). However, NFSI proved to provide faster and
higher yielding reactions (Scheme 4), giving fluorinated b-ketoest-
ers 20 and 21 in 61% and 64% yields, respectively.
The new carbohydrate bipyridine hybrids were then used in the
same reaction, using ketoester 18 and 19 as well as the benzyltetr-
alone substrate 22 (Scheme 5, Table 1). Chiral diesters were evalu-
ated first, giving good yields of fluorinated compounds 20, 21 and
23. In terms of enantioselectivity, the results were compared to
those arising from other chiral systems: a bipyridine dicarboxylic
ester derived from (ꢀ) menthol 24 (prepared by the same method)
and two bis-oxazolines, Box 1 and Box 2, known as efficient chelates
for Cu(II) already used in asymmetric electrophilic fluorination.26
Glucofuranose derivative 7 gave modest enantiomeric excesses
(up to 27% ee) that were comparable to those obtained with Box 1
(32% ee) under exactly the same conditions. It should be noted that
the latter Box ligands can give excesses up to 85% in other condi-
tions, notably using more constrained substrates.26 Also, better re-
sults were reported using ether results in Et2O as solvent, though in
the case of the new bipyridine ligands described here, no improve-
ment of the ee was observed compared to CH2Cl2. With the allofu-
ranose derivative 8, a reversal of the enantioselectivity was
observed, in a modest though significant pseudo-enantiomeric
effect.
The ability of the 2,20-bipyridine-3,30-dicarboxylic scaffold to
catalyse the fluorination of b-ketoesters with N-fluoro-bis-(benze-
nzesulfonyl)imide (NFSI) as a fluorinating agent was first checked
The influence of temperature and of the metal was investigated
in the case of the reactions of ketoester 19 using ligand 7 (Tables 2

596
A. Assalit et al. / Tetrahedron: Asymmetry 20 (2009) 593–601
HOBt/ EDCI
HCl
O
O
O
O
O
O
O
O
O
H2N
O
HN
N
O
2eq.
CO2H
N
12
Et3N (2eq.),
DCM dry, rt
(47%)
N
2
HO2C
6
O
O
Et3P (2.2eq.),
Toluene 80°C
O
O
O
NH
O
O
O
O
O
15
(21%)
O
2
N3
N
2
O
OAc
O
N
O
O
O
O
N
O
HN
AcO
AcO
OAc
O
O
HN
HN
O
O
O
O
O
2
N
2
13
14
(24%)
16
(26 %)
(30%)
Scheme 3. Synthesis of diamides 12–16.
and 3). Lowering the temperature was found to have a limited,
though consistent, effect on the ee, but the reaction became too
slow to be performed conveniently. Regarding the metal, copper(II)
triflate clearly gave the fastest reactions and best enantioselectivity
than Zn, Ni and Pd. Unlike in the case of Shibata0s system,26b addi-
tion of Ni(ClO4)2 did not improve the ee (entry 4). Moreover La, Sc
and Yb, did not deliver any ee, likely because of their lower ability
to form tetradentate complexes, unlike the other group of metals.29
The geometry of the new complexes was not determined, however,
planar or pseudo planar tetradentate structures are those mostly
reported in the literature for copper 2,20-bipyridine-3,30-disubsti-
tuted systems,30 though octaedric structures have also been found
in a polymeric chloranilate complex.31 In most examples, the
bipyridine adopts a cis conformation, though a trans conformation
was also suggested.28,30b,32
glucose amide 12 was reversed compared to that for the glucose
ester 7 (ee in the same range) and in this case, the glucose and
allose systems led to the same major enantiomer, without any
pseudo-enantiomeric effect. A significant 20% ee, again towards
the same enantiomer, was observed in the case of the galact-
ose-based amide ligand 16, whereas the corresponding ester 11
led to no measurable selectivity. The fructose amide gave no
selectivity, neither the secondary amide derived from glucosa-
mine 14, though more constraint. These results show that the
presence of the two extra nitrogen atoms contributes to the
geometry of the intermediate complex, even though the amide
nitrogen atoms, being protonated, are not believed to be involved
in the coordination of the metal. Indeed, deprotonation has been
shown to be critical for such a participation of amides in metal
complexation.33
Finally, the five bipyridine sugar hybrids connected via an
amide link 12–16 were evaluated as ligands, using b-ketoester 21
which gave the best results with ester ligands (Table 4), only using
copper as the metal which proved to give the best results.
Fluorination using the amide catalysts proceeded in similar
yields as for esters. Regarding the enantioselectivity, some differ-
ences were observed compared to esters. The selectivity for the
5. Conclusion
The first examples of chiral 2,20-bipyridine-3,30-dicarboxylic
acid carbohydrate esters and amides have been prepared and used
as chiral ligands in the Cu(II)-mediated electrophilic fluorination
reaction. A first observation is that this type of bipyridine is able

A. Assalit et al. / Tetrahedron: Asymmetry 20 (2009) 593–601
597
1) Cu(OTf)2 (10% mol.)
O
O
O
2)
OEt
O
Ph
O
or
O
18
F
O
MeO2C
N
CO2Me
N
O
19
F
OEt
or
O
Ph
O
3) NFSI
CH2Cl2, r.t.
21
(64%)
20 (61%)
17
(12% mol.)
Cl
N
"F+" =
N
F
"F+" =
SO2Ph
SO2Ph
-
N
F
2 BF4
-
F
N
NFSI :
N
2 BF4
F
in CH2Cl2 : 21: traces after 13d
in CH3CN : 21 : 42% after 6d
in CH2Cl2 : 21 : 63% after 3d
21
in CH3CN :
: 42% after 3d
Scheme 4. Electrophilic fluorination mediated by 17.
to catalyse the reaction. In terms of asymmetric induction, modest
enantiomeric excesses were obtained compared to those obtained
through the best literature reports. However, the selectivity was
found to be in a similar range as those obtained, under identical
conditions, using other systems previously described. The simplic-
ity of the overall synthetic sequence from ortho-phenanthroline
and the availability of carbohydrate derivatives are the main
advantages of these new ligands.
6. Experimental
6.1. General
CH2Cl2 was dried over molecular sieves before use. Other re-
agents were used as received. NMR spectra were recorded with a
Bruker Avance 300 instrument. 1H, 13C and 19F NMR spectra were
recorded in CDCl3 at 300, 75 and 282 MHz, respectively. Chemical
1) Cu(OTf)2
(10% mol.)
2) β−keto-ester
18,19, 22
O
O
RO2C
N
CO2R
N
F
R1
O
3) NFSI
∗
CH2Cl2, r.t.
n
Chiral ligands
(12% mol.)
O
X
O
O
O
O
X
X
OEt
O
Ph
O
Ph
O
19
21
: X = H
: X = F
18 : X = H
20 : X = F
22
23
: X = H
: X = F
O
O
O
O
O
O
N
N
N
N
tBu
tBu
Ph
Ph
Box 1
Box 2
N
2
24
Scheme 5. Asymmetric fluorination of b-ketoesters with new chiral ligands.

598
A. Assalit et al. / Tetrahedron: Asymmetry 20 (2009) 593–601
Table 1
Table 3
Asymmetric fluorination of b-ketoesters 18, 19 and 22 with ligands 7–11 and 24
Metal effect on asymmetric 7-mediated fluorination of 19
Entry
1
Ligands
20a
21a
23a
Entry
Metallic catalyst
Yielda (%)
ee (%)
Reaction time
7
75%
(9%)
n.d.
77%
54%
1
2
3
4
5
6
7
Cu(OTf)2
Zn(OTf)2
PdCl2
77
68
42
77
68
71
80
27
15
9
10
0.5
0.5
1
Overnight
5 days
(27%)
57%
(18%)
62%
2
3
4
5
6
7
8
8
8 daysb
(14%)b
68%
(9%)b
47%
Ni(ClO4)2ꢁ2H2O
Overnight
2.5 days
1.75 days
9
84%
(<5%)
63%
Sc(OTf)3
(<5%)
82%
(<5%)
59%
(<5%)
64%
(<5%)
60%
(<5%)
70%
(<5%)
Yb(OTf)3ꢁ2H2O
La(OTf)3
b
10
2 weeks
(<5%)
a
Isolated yields.
Incomplete conversion.
11
b
24
67%
(<5%)
78%
(17%)
50%
(5%)
67%
(<5%)
55%
(27%)
60%
(<5%)
Box 1
Box 2
4.03–3.89 (m, 6H), 1.47 (s, 6H), 1.36 (s, 6H), 1.27 (s, 6H), 1.25 (s,
6H). 13C NMR: d = 164.4, 151.9, 151.9, 138.6, 125.4, 123.1, 112.4,
109.6, 105.0, 83.0, 79.8, 77.4, 72.2, 67.4, 26.9, 26.7, 26.3, 25.4. Anal.
Calcd for C36H44N2O14: C, 59.33; H, 6.09. Found: C, 59.52; H, 5.98.
(32%)
68%
(7%)
a
Isolated yields. In parentheses: ee.
Other enantiomer as major product.
b
6.4. Bis(3-deoxy-1,2:5,6-di-O-isopropylidene-a-D-allofuranos-
3-yl)-2,20-bipyridine-3,30-dicarboxylate 8
shifts are given in ppm relative to TMS (1H, 13C) or CFCl3 (19F) as an
internal reference. Coupling constants are given in Hertz. Flash
chromatography was performed on silica gel 60 M (0.04–
0.063 mm).
Melting points (uncorrected) were determined in capillary
tubes on a Büchi apparatus. IR spectra were recorded on a Perkin
Elmer Spectrum One FTIR spectrometer; spectral width of 4000–
400 cmꢀ1 was set with 4 cmꢀ1 resolution. Optical rotations were
measured with a Perkin–Elmer 241 polarimeter at room tempera-
ture. The enantiomeric excesses (ee) were determined by chiral
HPLC (Chiralcel OJ-H column; hexane/iPrOH and/or ChiralpakÒ
AD-HTM). Starting carbohydrates derivatives (partially protected
alcohols, amines and azides) are all known compounds either
available commercially or prepared by standard procedures.
White solid. [a]D = + 138 (c 0.5, CHCl3); mp 126–127 °C;
LRMS(ESI) m/z for C36H45N2O14 (M+H)+ = 729.1; HRMS (ESI) m/z
calculated (M+H)+ 729.28653, found 729.28758; 1H NMR:
d = 8.71 (dd, J = 4.8, J = 1.6, 2H), 8.33 (dd, J = 7.9, J = 1.6, 2H), 7.42
(dd, J = 7.9, J = 4.8, 2H), 5.72 (d, J = 3.7, 2H), 4.91 (dd, J = 4.8,
J = 8.8, 2H), 4.70 (dd, J = 3.7, J = 4.8, 2H), 4.17 (ddd, J = 6.3, J = 7.0,
J = 3.7, 2H), 3.95 (dd, J = 8.6, J = 7.0, 2H), 3.94 (dd, J = 8.8, J = 3.6,
2H), 3.77 (dd, J = 8.6, J = 6.3, 2H), 1.47 (s, 6H), 1.34 (s, 6H), 1.28
(s, 6H), 1.24 (s, 6H). 13C NMR: d = 164.7, 158.8, 151.6, 138.4,
125.3, 122.8, 113.2, 109.6, 103.9, 77.6, 77.1, 74.7, 72.8, 65.0, 26.8,
26.6, 26.2, 25.1. Anal. Calcd for C36H44N2O14: C, 59.33; H, 6.09.
Found: C, 59.17; H, 6.17.
6.5. Bis(1-deoxy-2,3:4,5-di-O-isopropylidene-b-D-fructopyranos-
1-yl)-2,20-bipyridine-3,30-dicarboxylate 9
6.2. Typical procedure for the preparation of chiral ligands
7–11, 17, 24
White foam. [
a
]
D = ꢀ12 (c 0.5, CHCl3); mp 85–89 °C; LRMS(ESI)
m/z for C36H45N2O14 (M+H)+ = 729.1; HRMS (ESI) m/z calculated
(M+H)+ 729.28653, found 729.28759; 1H NMR: d = 8.74 (dd,
J = 4.8, J = 1.6, 2H), 8.34 (dd, J = 7.9, J = 1.6, 2H), 7.40 (dd, J = 7.9,
J = 4.8, 2H), 4.54 (dd, J = 7.9, J = 2.6, 2H), 4.46 (d, J = 11.7, 2H),
4.19 (bdd, J = 7.9, J = 0.8, 2H), 4.14 (d, J = 2.6, 2H), 4.04 (d, J = 11.7,
2H), 3.85 (dd, J = 13.0, J = 1.7, 2H), 3.70 (dd, J = 13.0, J = 0.8, 2H),
1.45 (s, 6H), 1.38 (s, 6H), 1.29 (s, 6H), 1.22 (s, 6H). 13C NMR:
d = 165.1, 158.7, 151.6, 138.0, 125.8, 122.7, 109.1, 108.8, 101.3,
70.8, 70.3, 70.0, 65.8, 61.3, 26.5, 25.9, 25.4, 24.1. Anal. Calcd for
C36H44N2O14: C, 59.33; H, 6.09. Found: C, 59.61; H, 6.41.
The alcohol (1.5 mmol) was added to a solution of 2,20-bipyri-
dine-3,3-dicarboxylic acid (6, 0.5 mmol) in dry dichloromethane
(3 mL). DMAP (2 mmol) and EDCI HCl (2 mmol) were then added,
and the mixture was stirred overnight. The reaction mixture was
washed with NH4Cl (saturated aqueous solution) and water, dried
over MgSO4 and the solvents were evaporated in vacuo. The crude
product was purified by flash chromatography when necessary.
6.3. Bis(3-deoxy-1,2:5,6-di-O-isopropylidene-
a-D-glucofuranos-
3-yl)-2,20-bipyridine-3,30-dicarboxylate 7
6.6. Bis(5-deoxy-1-O-methyl,2,3-O-isopropylidene-b-D-ribofur-
White solid. IR
m
(C@O) = 1732 cmꢀ1; [
a]
D = ꢀ67 (c 0.5, CHCl3);
anos-5-yl)-2,2’-bipyridine-3,30-dicarboxylate 10
mp 163–167 °C; LRMS(ESI) m/z for C36H45N2O14 (M+H)+ = 729.1;
HRMS (ESI) m/z calculated (M+H)+ 729.28653, found 729.28686;
1H NMR: d = 8.78 (dd, J = 4.9, J = 1.7, 2H), 8.35 (dd, J = 8.0, J = 1.7,
2H), 7.48 (dd, J = 8.0, J = 4.9, 2H), 5.62 (d, J = 3.8, 2H), 5.27 (d,
J = 2.8, 2H), 4.34 (d, J = 3.8, 2H), 4.11 (dd, J = 7.9, J = 2.8, 2H),
Colorless oil. [
a]
D = ꢀ45 (c 0.5, CHCl3); LRMS(ESI) m/z for
C30H37N2O12 (M+H)+ = 617.1; HRMS (ESI) m/z calculated (M+H)+
617.23410, found 617.23479; 1H NMR: d = 8.75 (br d, J = 4.5, 2H),
Table 4
Table 2
Asymmetric fluorination of 19 with ligands 12–16a
Temperature effect on asymmetric 7-mediated fluorination of 19
Yielda (%)
ee (%)
Entry
1
2
3
4
5
6
7
Entry
Temperature (°C)
Ligands
12
13
14
15
16
Box 1
Box 2
1
2
3
rt
0
ꢀ28
77
76
27
29
32
21a
70%
68%
78%
75%
(<5%)
75%
60%
(32%)
68%
(7%)
(23%)b
(19%)b
(6%)b
(20%)b
75b
a
a
Isolated yields. In parentheses: ee.
Other enantiomer as major product (compared to ligand 7).
Isolated yields.
Incomplete conversion after 8 days.
b
b

A. Assalit et al. / Tetrahedron: Asymmetry 20 (2009) 593–601
599
8.42 (dd, J = 7.9, J = 1.3, 2H), 7.44 (dd, J = 7.9, J = 4.5, 2H), 4.89 (br s,
2H), 4.51 (d, J = 5.8, 2H), 4.41 (d, J = 5.8, 2H), 4.13–4.05 (m, 6H),
3.24 (s, 6H), 1.44 (s, 6H), 1.28 (s, 6H). 13C NMR: d = 165.0, 159.6,
151.9, 138.7, 132.6, 122.9, 112.6, 109.4, 85.1, 83.8, 81.8, 65.3,
55.0, 26.5, 25.0. Anal. Calcd for C30H36N2O12: C, 58.44; H, 5.88.
Found: C, 58.18; H, 6.05.
6H), 1.34 (s, 6H), 1.29 (s, 6H), 1.21 (s, 6H). 13C NMR: d = 167.8,
156.2, 150.0, 136.5, 131.8, 123.3, 112.0, 109.8, 104.6, 84.2, 78.9,
72.6, 67.4, 53.5, 27.1, 26.9, 26.4, 25.7.
6.12. N,N0-Bis-(3-deoxy-1,2 :5,6-di-O-isopropylidene-
allofuranos-1-yl)-2,20-bipyridine-3,30-carboxamide 13
a-D-
6.7. Bis(6-deoxy-1,2:3,4-di-O-isopropylidene-
a
-
D
-galactopyranos-
White solid. [a]D = + 48 (c 0.5, CHCl3); mp 120–122 °C; LRMS(E-
6-yl)-2,20-bipyridine-3,30-dicarboxylate 11
SI) m/z for C36H47N4O12 (M+H)+ = 727.1; HRMS (ESI) m/z calculated
(M+H)+ 727.318499, found 727.316524; 1H NMR: d = 8.65 (dd,
J = 4.8, J = 1.6, 2H), 7.99 (dd, J = 7.8, J = 1.6, 2H), 7.41 (dd, J = 7.8,
J = 4.8, 2H), 7.09 (br d, J = 9.2, 2H), 5.76 (d, J = 3.6, 2H), 4.40 (dd,
J = 4.8, J = 3.6, 2H), 4.17 (td, J = 9.3, J = 4.8, 2H), 4.05 (td, J = 6.5,
J = 3.6, 2H), 3.98 (dd, J = 8.0, J = 6.5, 2H), 3.85 (dd, J = 8.0, J = 6.5,
2H), 3.75 (dd, J = 9.3, J = 3.6, 2H), 1.44 (s, 6H), 1.38 (s, 6H), 1.32
(s, 6H), 1.26 (s, 6H). 13C NMR: d = 167.6, 156.5, 150.3, 136.3,
132.0, 123.3, 112.6, 109.7, 104.4, 79.0, 78.5, 75.4, 64.7, 53.3, 26.7,
26.5, 26.4, 25.5.
White solid. [
a
]
D = ꢀ46 (c 0.5, CHCl3); mp 153–154 °C; LRMS(E-
SI) m/z for C36H45N2O14 (M+H)+ = 729.0; HRMS (ESI) m/z calculated
(M+H)+ 729.28653, found 729.28756; 1H NMR: d = 8.68 (br d,
J = 4.8, 2H), 8.33 (dd, J = 7.8, J = 1.4, 2H), 7.39 (dd, J = 7.8, J = 4.8,
2H), 5.41 (d, J = 4.9, 2H), 4.51 (dd, J = 7.9, J = 2.3, 2H), 4.24–4.12
(m, 6H), 3.99 (dd, J = 7.9, J = 1.7, 2H), 3.84 (br td, J = 1.7, J = 6.4,
2H), 1.41 (s, 6H), 1.37 (s, 6H), 1.27 (s, 6H), 1.25 (s, 6H). 13C NMR:
d = 165.3, 159.1, 151.5, 138.4, 125.5, 122.6, 109.4, 108.6, 96.0,
70.7, 70.5, 70.4, 65.4, 63.8, 26.0, 25.9, 24.9, 24.4. Anal. Calcd for
C36H44N2O14: C, 59.33; H, 6.09. Found: C, 59.61; H, 6.01.
6.13. N,N0-Bis-(1,3,4,6-tetra-O-acetyl-2-deoxy-b-
D-glucopyranos-
1-yl)-2,20-bipyridine-3,30-carboxamide 14
6.8. Dimethyl 2,20-bipyridine-3,30-dicarboxylate 17
White gum. [a]D = + 30 (c 0.5, CHCl3); LRMS(ESI) m/z for
White solid. Mp 155–156 °C; LRMS(ESI) m/z for C14H13N2O4
(M+H)+ = 273.1; HRMS (ESI) m/z calculated (M+H)+ 273.08698,
found 273.08699; 1H NMR: d = 8.69 (dd, J = 4.8, J = 1.65, 2H), 8.31
(dd; J = 8.0, J = 1.65, 2H), 7.39 (dd, J = 8.0, J = 4.8, 2H), 3.64 (s, 6H).
13C NMR: d = 166.4, 159.7, 151.9, 138.5, 125.8, 123.1, 52.6.
C40H48N4O20 (M+H)+ = 903.1; HRMS (ESI) m/z calculated (M+H)+
903.2784, found 903.2805; 1H NMR: d = 8.52 (dd, J = 4.8, J = 1.5,
2H), 7.97 (d, J = 8.8, 2H), 7.87 (dd, J = 7.8, J = 1.5, 2H), 7.34 (dd,
J = 7.8, J = 4.8, 2H), 5.59 (d, J = 8.8, 2H), 5.18 (t, J = 9.8, J = 9.8, 2H),
5.00 (t, J = 9.8, J = 9.8, 2H), 4.21 (dd, J = 12.4, J = 4.3, 2H), 4.17–4.08
(m, 2H), 4.03 (dd, J = 12.4, J = 2.1, 2H), 3.80 (ddd, J = 9.8, J = 4.3,
J = 2.1, 2H), 2.02 (s, 12H), 1.96 (s, 6H), 1.95 (s, 6H), 1.26 (s, 6H).
13C NMR: d = 170.5, 170.4, 169.2, 169.0, 168.1, 156.1, 149.8, 136.2,
130.8, 123.2, 91.9, 72.3, 72.0, 68.2, 61.6, 53.2, 20.9, 20.6, 20.5.
6.9. Bis[(2R,5S)-5-methyl-2-(1-methylethyl)cyclohexyl]2,20-
bipyridine-3,30-dicarboxylate 24
Yellow solid. [
a
]
D = ꢀ50 (c 0.5, CHCl3); mp 90–93 °C; LRMS(ESI)
m/z for C32H45N2O4 (M+H)+ = 521.2; HRMS (ESI) m/z calculated
(M+H)+ 521.33738, found 521.33714; 1H NMR: d = 8.77 (dd,
J = 4.9, J = 1.7, 2H), 8.46 (dd, J = 7.9, J = 1.7, 2H), 7.48 (dd, J = 7.9,
J = 4.9, 2H), 4.71 (td, J = 10.6, J = 10.6, J = 4.3, 2H), 1.86 (m, 2H),
1.60–1.50 (m, 6H), 1.35 (m, 2H), 0.99–0.56 (m, 26H). 13C NMR:
d = 164.8, 159.8, 151.4, 138.6, 125.6, 122.6, 75.3, 46.8, 40.5, 34.1,
31.3, 25.6, 22.8, 22.0, 21.0, 15.8. Anal. Calcd for C32H44N2O4: C,
73.81; H, 8.52. Found: C, 73.59; H, 8.77.
6.14. General procedure for azide coupling: preparation of
chiral ligands 15 and 16
6.14.1. Azide coupling
2,20-Dipyridine-3,30-dicarboxylic acid (61 mg, 0.25 mmol,
1 equiv) was dissolved in toluene (1.5 mL) under a nitrogen atmo-
sphere. The azide (0.5 mmol, 2 equiv) and triethylphosphine
(550 lL, 1 M in THF, 0.55 mmol, 2.2 equiv) were premixed in tolu-
ene (1 mL) for two minutes and were then added to the reaction
mixture. The resulting solution was heated at 80 °C. The organic
layer was then washed several times with water. The crude prod-
uct was dried over MgSO4 and was purified by flash chromatogra-
phy to give the corresponding 2,20-bipyridine-3,30-carboxamide.
6.10. General procedure for amine coupling: preparation of
chiral ligands 12–14
2,20-Dipyridine-3,30-dicarboxylic acid (0.25 mmol, 1 equiv) was
dissolved in dry dichloromethane (3 mL) under a nitrogen atmo-
sphere. Hydroxybenzotriazole (HOBt, 101 mg, 0.75 mmol, 3 equiv)
and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochlo-
ride salt (144 mg, 0.75 mmol, 3 equiv) were then added. The reac-
6.15. N,N0-Bis-(1-deoxy-2,3:4,5-di-O-isopropylidene-b-
D-fructo-
pyranos-1-yl)-2,20-bipyridine-3,30-carboxamide 15
tion mixture was cooled in an ice bath and triethylamine (70
l
L,
White gum.
[
a
]
D = ꢀ31 (c 1.0, CHCl3); LRMS(ESI) m/z for
0.5 mmol, 2 equiv) was added. Finally, the amine (0.5 mmol,
2 equiv) was added. The organic layer was then washed with
water. The crude product was dried over MgSO4 and was purified
by flash chromatography to give the corresponding 2,20-bipyri-
dine-3,30-carboxamide.
C36H48N4O12 (M+H)+ = 727.1; HRMS (ESI) m/z calculated (M+H)+
727.3190, found 727.3185; 1H NMR: d = 8.65 (dd, J = 4.8, J = 1.6,
2H), 8.04 (dd, J = 7.9, J = 1.6, 2H), 7.37–7.30 (m, J = 7.9, J = 4.8,
4H), 4.51 (dd, J = 7.8, J = 2.5, 2H), 4.18–4.16 (m, J = 2.5, 4H), 3.79
(dd, J = 13.1, J = 2.0, 2H), 3.68–3.63 (m, 4H), 3.40 (dd, J = 13.8,
J = 5.0, 2H), 1.48 (s, 6H), 1.33 (s, 6H), 1.30 (s, 12H).13C NMR:
d = 167.7, 155.7, 149.8, 136.5, 132.3, 122.8, 109.1, 108.4, 102.3,
71.8, 70.6, 70.2, 61.4, 41.2, 26.2, 25.8, 25.0, 24.1.
6.11. N,N0-Bis-(3-deoxy-1,2:5,6-di-O-isopropylidene-
glucofuranos-1-yl)-2,20-bipyridine-3,30-carboxamide 12
a-D-
White solid. [
a]
D = ꢀ39 (c 0.5, CHCl3); mp 105–109 °C; LRMS(E-
6.16. N,N0-Bis-(6-deoxy-1,2:3,4-di-O-isopropylidene-
a-D-galacto-
SI) m/z for C36H46N4O12Na (M+Na)+ = 749.2; HRMS (ESI) m/z calcu-
lated (M+Na)+ 749.30099, found 749.30112; 1H NMR: d = 8.57 (dd,
J = 4.8, J = 1.6, 2H), 8.00–7.93 (m, J = 7.7, J = 7.8, J = 1.6, 4H) 7.32 (dd,
J = 7.8, J = 4.8, 2H), 5.38 (d, J = 3.5, 2H), 4.31 (dd, J = 7.7, J = 3.6, 2H),
4.16 (d, J = 3.5, 2H), 4.01–3.98 (m, 4H), 3.84–3.76 (m, 4H), 1.44 (s,
pyranos-6-yl)-2,20-bipyridine-3,30-carboxamide 16
White solid. [
a]D = ꢀ19 (c 0.5, CHCl3); mp 123–125 °C; LRMS(E-
SI) m/z for C36H48N4O12 (M+H)+ = 727.1; HRMS (ESI) m/z calculated
(M+H)+ 727.3190, found 727.3201; 1H NMR: d = 8.63 (dd, J = 4.9,

600
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J = 1.6, 2H), 7.98 (dd, J = 7.8, J = 1.6, 2H), 7.44 (t, J = 5.2, 2H), 7.36
(dd, J = 7.8, J = 4.9, 2H), 5.41 (d, J = 5.0, 2H), 4.53 (dd, J = 7.9,
J = 2.3, 2H), 4.26 (dd, J = 5.0, J = 2.3, 2H), 3.98 (dd, J = 1.8, J = 7.9,
2H), 3.86 (m, 2H), 3.51 (ddd, J = 13.7, J = 6.4, J = 5.2, 2H), 3.30
(ddd, J = 13.7, J = 6.4, J = 5.2, 2H), 1.46 (s, 6H), 1.41 (s, 6H), 1.30 (s,
12H).13C NMR: d = 168.5, 156.3, 150.2, 136.6, 132.5, 123.3, 109.7,
109.1, 96.6, 71.7, 71.1, 70.9, 66.0, 40.8, 26.4, 26.3, 25.4, 24.7.
6.17. Typical procedure for electrophilic fluorination
Ligands 7–11 and 24 or 12–16 (0.03 mmol) and copper(II) tri-
flate (0.025 mmol) were premixed in dry dichloromethane, for
2 h, under a nitrogen atmosphere. The b-ketoester 18, 19, or 22
(0.25 mmol) was then added followed by NFSI (0.375 mmol) and
the reaction was monitored by TLC and 19F NMR. At the end of
the reaction, the solvent was removed under vacuum and the prod-
uct was purified by flash chromatography. Chiral HPLC led to two
distinctive peaks, the second one being the major enantiomer for
esters in most cases except for ligand 8, and the first one being
the major for all sugar amide ligands. The absolute configuration
11. (a) Kirk, K. L. Curr. Top. Med. Chem. 2006, 6, 1447–1456; (b), 6th ed.Burger’s
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,
R,R-Box1-catalysed fluorination of ketoester 22 was found to give
the (+) isomer as major product. By analogy to these results the
(ꢀ) sign is believed to be major enantiomer based on our reference
experiment using (S,S)-Box 1.
13. Smart, B. E. J. Fluorine Chem. 2001, 109, 3–11.
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6.18. Ethyl 2-fluoro-2-benzylacetoacetate 20
Colorless oil. 1H NMR: d = 7.31–7.22 (m, 5H), 4.24 (q, J = 7.1, 2H),
3.45 (dd, J = 25.4, J = 14.8, 1H), 3.39 (dd, J = 25.4, J = 14.8, 1H), 2.15
(d, J = 5.2, 3H), 1.26 (t, J = 7.1). 13C NMR: d = 202.8 (d, JC–F = 29.6),
166.1(d, JC–F = 25.8), 133.5, 130.8 (d, JC–F = 1.1), 128.8, 127.8,
100.4 (d, JC–F = 200.3), 63.1, 40.2 (d, JC–F = 20.3), 26.7, 14.3. 19F
NMR: d = ꢀ165.07 (tq, J = 25.4, J = 5.2). Anal. Calcd for C13H15FO3:
C, 65.53; H, 6.35. Found: C, 65.36; H, 6.59.
16. Dolbier, W. R., Jr. J. Fluorine Chem. 2005, 126, 157–163.
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6.19. Benzyl 1-fluoro-2-oxo-cyclopentanecarboxylate 21
18. (a) Chambers, R. Fluorine in Organic Chemistry; Blackwell Publishing: Oxford,
2004; (b)Chemistry of Organic Fluorine Compounds II. A Critical Review; Hudlicky,
M., Pavlath, A. E., Eds.; American Chemical Society: Washington, DC, 1995.
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Angew. Chem., Int. Ed. 2006, 45, 2172–2174.
Yellow oil. 1H NMR: d = 7.35–7.34 (m, 5H), 5.28 (d, J = 12.1, 1H),
5.22 (d, J = 12.1, 1H), 2.62–2.48 (m, 3H), 2.35 (m, 1H), 2.11 (m, 2H).
13C NMR: d = 207.4 (d, JC–F = 16.5), 167.4 (d, JC–F = 27.4), 135.1,
129.11, 129.07, 128.6, 94.8 (d, JC–F = 200.3), 68.2, 36.1, 34.0 (d, JC–
F = 20.8), 18.5 (d, JC–F = 3.3). 19F NMR: d = ꢀ164.4 (t, J = 20.8). Anal.
Calcd for C13H13FO3: C, 66.09; H, 5.55. Found: C, 66.18; H, 5.47.
21. (a) Jensen, B. S. CNS Drug Rev. 2002, 8, 353–360; (b) Young, B. L.; Cooks, R. G.;
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2007, 43, 1602–1608.
6.20. Benzyl 2-fluoro-1-tetralone-2-carboxylate 23
22. (a) Shibata, N.; Ishimaru, T.; Suzuki, E.; Kirk, K. L. J. Org. Chem. 2003, 68, 2494–
2497; (b) Zoute, L.; Audouard, C.; Plaquevent, J.-C.; Cahard, D. Org. Biomol.
Chem. 2003, 1, 1833–1834.
23. Haffner, C. D.; McDougald, D. L.; Reister, S. M.; Thompson, B. D.; Conlee, C.;
Fang, J.; Bass, J.; Lenhard, J. M.; Croom, D.; Secosky-Chang, M. B.; Tomaszek, T.;
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25. (a) Hintermann, L.; Togni, A. Angew. Chem., Int. Ed. 2000, 39, 4359–4362; (b)
Hamashima, Y.; Yagi, K.; Takano, H.; Tamás, L.; Sodeoka, M. J. Am. Chem. Soc.
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Yellow oil. 1H NMR: d = 8.10 (m, 1H), 7.57 (m, 1H), 7.42–7.26
(m, 7H), 5.33 (d, J = 12.4, 1H), 5.24 (d, J = 12.4, 1H), 3.15 (m, 1H),
3.02 (m, 1H), 2.74 (m, 1H), 2.56 (m, 1H). 13C NMR: d = 188.6 (d,
JC–F = 18.7), 167.3 (d, JC–F = 26.3), 143.2, 135.1, 135.0, 131.0, 129.2,
129.0, 128.92, 128.86, 128.4, 127.7, 93.4 (d, JC–F = 193.7), 67.8,
32.0 (d, JC–F = 22.5), 24.9 (d, JC–F = 7.1). 19F NMR: d = ꢀ164.9 (dd,
J = 22.9, J = 11.5). Anal. Calcd for C18H15FO3: C, 72.47; H, 5.07.
Found: C, 72.86; H, 5.38.
Acknowledgments
26. (a) Ma, J.-A.; Cahard, D. Tetrahedron: Asymmetry 2004, 15, 1007–1011; (b)
Shibata, N.; Ishimaru, T.; Nagai, T.; Kohno, J.; Toru, T. Synlett 2004, 1703–1706.
27. (a) Enders, D.; Hüttl, M. R. M. Synlett 2005, 6, 991–993; (b) Marigo, M.;
We thank the CNRS and GSK for their financial support and Dr.
P. Boullanger for nomenclature suggestions.
Fielenbach, D.; Braunton, A.; Kjꢀrsgaard, A.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2005, 44, 3703–3706; (c) Steiner, D. D.; Mase, N.; Barbas, C. F., III Angew.
Chem., Int. Ed. 2005, 44, 3706–3710; (d) Beeson, T. D.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 8826–8828.
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