Immobilization of bis(bipyridine) BINOL ligands and their use in chiral resolution

Article abstract of DOI:10.1021/ol901958v

An enantlomerlcally pure bls(blpyrldlne) BINOL ligand was synthesized which was functionalized with an Iodine substituent In Its periphery. Using this halogen function, the ligand was Immobilized on a commercially available polystyrene gel via Suzuki cross-coupling. The functlonallzed gel was found to be effective In the chiral resolution of similar bis(blpyrldlne) ligands based on a Troeger's base core.

Full text of DOI:10.1021/ol901958v

ORGANIC
LETTERS
2
009
Vol. 11, No. 21
786-4789
Immobilization of Bis(Bipyridine) BINOL
Ligands and Their Use in Chiral
Resolution
4
Jens Bunzen, Ulf Kiehne, Christian Benkh a¨ user-Schunk, and Arne L u¨ tzen*
Kekul e´ Institut f u¨ r Organische Chemie und Biochemie, Rheinische
Friedrich-Wilhelms-UniVersit a¨ t Bonn, Gerhard-Domagk-Strasse 1,
D-53121 Bonn, Germany
arne.luetzen@uni-bonn.de
Received June 12, 2009
ABSTRACT
An enantiomerically pure bis(bipyridine) BINOL ligand was synthesized which was functionalized with an iodine substituent in its periphery.
Using this halogen function, the ligand was immobilized on a commercially available polystyrene gel via Suzuki cross-coupling. The functionalized
gel was found to be effective in the chiral resolution of similar bis(bipyridine) ligands based on a Tr o¨ ger’s base core.
The last two decades have witnessed an enormous develop-
ment in the field of helicates. Besides the appealing beauty
lecular aggregates. Recently, however, functional aspects of
helicates came into focus such as, e.g., their interaction with
DNA.
1
4
of these inherently chiral metallo-supramolecular compounds,
one of the reasons for this interest is that the helicates can
Some time ago, we were able to synthesize a bis(bipyri-
dine) BINOL ligand and demonstrate its diastereoselective
1
f,2
be used as model systems to study cooperative effects or
3
5
(
dia-)stereoselective self-assembly processes of supramo-
self-assembly into dinuclear helicates. Thus, we thought to
make use of the chiral information of this ligand to
(
1) Recent reviews: (a) Albrecht, M. Chem. ReV. 2001, 101, 3457. (b)
Mamula, O.; von Zelewsky, A. Coord. Chem. ReV. 2003, 242, 87. (c)
Hannon, M. J.; Childs, L. J. Supramol. Chem. 2004, 16, 7. (d) Costisor,
O.; Linert, W. Inorg. Chem. 2005, 17, 289. (e) Miyake, H.; Tsukube, H.
Supramol. Chem. 2005, 17, 53. (f) Piguet, C.; Borkovec, M.; Hamacek, J.;
Zeckert, K. Coord. Chem. ReV. 2005, 249, 705. (g) Albrecht, M. Top. Curr.
Chem. 2005, 248, 105. (h) Albrecht, M.; Fr o¨ hlich, R. Bull. Chem. Soc. Jpn.
(2) Some recent examples: (a) Zeckert, K.; Hamacek, J.; Senegas, J.-
M.; Dalla-Favera, N.; Floquet, S.; Bernardinelli, G.; Piguet, C. Angew.
Chem., Int. Ed. 2005, 44, 7954. (b) Hamacek, J.; Borovec, M.; Piguet, C.
J. Chem. Soc., Dalton Trans. 2006, 1473. (c) Hamacek, J.; Piguet, C. J.
Phys. Chem. B 2006, 110, 7783. (d) Canard, G.; Piguet, C. Inorg. Chem.
2007, 46, 3511. (e) Dalla-Favera, N.; Hamacek, J.; Borovec, M.; Jeannerat,
D.; Gumy, F.; B u¨ nzli, J.-C. G.; Ercolani, G. Chem.sEur. J. 2008, 14, 2994.
2
007, 80, 797. (i) He, C.; Zhao, Y.; Guo, D.; Lin, Z.; Duan, C. Eur. J. Inorg.
Chem. 2007, 3451.
10.1021/ol901958v CCC: $40.75
Published on Web 10/01/2009
 2009 American Chemical Society

implement a function in our helicates. In this paper, we report
on the synthesis of an immobilized enantiomerically pure
bis(chelating) ligand strand that could be used in a proof of
principle study for the resolution of a similar racemic
bis(chelating) ligand through liquid chromatography (LC)
presumably via diastereoselective helicate formation.
In order to prepare the boronated polystyrene, we followed
a procedure described by Hodge and Zhang. Bio-Beads S-X
6
1 from BIO-RAD was chosen as the starting material. After
cleaning of the commercial polymeric material following a
7
procedure described by Fr e´ chet and Farrall, the boronic acid
6
,8
function was introduced into the polystyrene backbone.
-Ethynyl-2,2′-bipyridine could be prepared in five steps
starting from 2-aminopyridine using a modified Negishi
5
8
,9
reaction as the key step.
Scheme 1. Retrosynthetic Analysis of Immobilized
The most effort, however, had to be spent on the synthesis
of the BINOL building block. As a first step, enantiomerically
pure (M)-BINOL was desymmetrized by introducing a
bromine substituent at the 6-position of the BINOL following
Bis(bipyridine) BINOL Ligand (M)-1
1
0
an approach of Cai et al.: one of the hydroxyl functions of
the BINOL was transformed into a pivaloyl ester. The bulky
ester group largely prevents acylation of the second hydroxyl
group due to steric hindrance. Thus, we obtained the desired
monoester in 91% yield and only 9% of the readily
crystallizing diester. Due to the deactivating ester group,
electrophilic bromination in dichloromethane at -78 °C
occurred only at the other naphthalene unit. After that, the
ester was saponified with sodium hydroxide solution and the
reactive hydroxyl functions were protected as methoxymethyl
ethers by a Williamson ether synthesis with methoxymethyl
8
,11
chloride ((M)-2).
Since the BINOL building block still needed to be
furnished with the two bipyridine units which we decided
to introduce before we immobilized the whole ligand on the
polymer, the bromine had to be masked in order to make
the following transformations regioselective. For this purpose,
To immobilize our ligand on a polymer gel, we had to
choose a suitable position to introduce an additional func-
tional group into the ligand structure that would allow us to
covalently link our ligand to the polymer. We decided to
use the 6-position of the BINOL-core for this purpose for
two reasons: First, it is far away from the bipyridines and
should not interfere with metal binding. Second, it can be
selectively addressed by an electrophilic attack. As shown
in Scheme 1, the synthesis of the immobilized ligand needed
three building blocks: a polystyrene furnished with boronic
acid ester groups, a protected BINOL equipped with (masked)
12
we adopted a protocol by Kobayashi et al. and exchanged
the bromine for a trimethylsilyl group affording BINOL (M)-
3
. (M)-3 was then lithiated in the 3,3′-position making use
of the ortho-directing effect of the acetal protecting groups
and subsequently quenched with iodine solution to give the
diiodinated building block ((M)-4) needed for the Sonogash-
ira coupling with 5-ethynyl-2,2′-bipyridine (5) (Scheme 2).
(
M)-4 and 5 were then coupled in a 2-fold Sonogashira
reaction to give (M)-6 in an excellent yield of 90% (Scheme
).
The next task was an ipso-substitution of the trimethylsilyl
group at the 6-position of the BINOL using iodine monochlo-
3
1
2
halide functions (X , X ), and an ethynylated 2,2′-bipyridine
that are coupled sequentially via cross-coupling procedures.
1
2
ride in order to reactivate this position for the final Suzuki
reaction. Interestingly, this turned out to be the most
challenging step in our synthesis. Optimization of the reaction
conditions finally allowed quantitative conversion of (M)-6
to the desired iodide (M)-7 without any byproducts (Scheme
(3) Some recent reviews about stereoselective self-assembly of supramo-
lecular aggregates: (a) Spector, M. S.; Selinger, J. V.; Schnur, J. M. Top.
Stereochem. 2003, 24, 281. (b) Hamilton, T. D.; MacGillivray, L. R. Cryst.
Growth Design 2004, 4, 419. (c) Mateos-Timoneda, M. A.; Crego-Calama,
M.; Reinhoudt, D. N. Chem. Soc. ReV. 2004, 33, 363. (d) Supramolecular
Chirality: Crego-Calama, M.; Reinhoudt, D. N. Top. Curr. Chem. 2006,
3
).
2
65. (e) Lee, S. L.; Lin, W. Acc. Chem. Res. 2008, 41, 521. For a more
comprehensive list of references on the diastereoselective self-assembly of
helicates, see references in: (f) Bunzen, J.; Bruhn, T.; Bringmann, G.; L u¨ tzen,
A. J. Am. Chem. Soc. 2009, 131, 3621, and ref 1i.
(6) Yuan, X.-Y.; Li, H.-Y.; Hodge, P.; Kilner, M.; Tastard, C. Y.; Zhang,
Z.-P. Tetrahedron: Asymmetry 2006, 17, 2401.
(
4) Review: (a) Hannon, M. J. Chem. Soc. ReV. 2007, 36, 280. Some
(7) Farrall, M. J.; Frechet, J. M. J. J. Org. Chem. 1976, 41, 3877.
recent examples: (b) Malina, J.; Hannon, M. J.; Brabec, V. Chem.sEur. J.
007, 13, 3871. (c) Pascu, G. I.; Hotze, A. C. G.; Sanchez-Cano, C.; Kariuki,
(8) See the Supporting Information for details.
2
(9) L u¨ tzen, A.; Hapke, M. Eur. J. Org. Chem. 2002, 2292. (b) Kiehne,
U.; Bunzen, J.; Staats, H.; L u¨ tzen, A. Synthesis 2007, 1061. (c) Hapke, M.;
B. M.; Hannon, M. J. Angew. Chem., Int. Ed. 2007, 46, 4374. (d) McDonell,
U.; Kerchoffs, J. M. C. A.; Castineiras, R. P. M.; Hicks, M. R.; Hotze,
A. C. G.; Hannon, M. J.; Rodger, A. J. Chem. Soc., Dalton. Trans. 2008,
Brandt, L.; L u¨ tzen, A. Chem. Soc. ReV. 2008, 37, 2782
(10) Cai, D.; Larsen, R. D.; Reider, P. J. Tetrahedron Lett. 2002, 43,
4055.
(11) Bai, X.-L.; Liu, X.-D.; Wang, M.; Kang, C.-Q.; Gao, L.-X. Synthesis
.
6
3
1
67. (e) Malina, J.; Hannon, M. J.; Brabe, V. Nucleic Acids Res. 2008, 36,
630. (f) Malina, J.; Hannon, M. J.; Brabec, V. Chem.sEur. J. 2008, 14,
0408.
2005, 458
.
(
5) L u¨ tzen, A.; Hapke, M.; Griep-Raming, J.; Haase, D.; Saak, W.
(12) Yamashita, Y.; Ishitani, H.; Shimizu, H.; Kobayashi, S. J. Am.
Chem. Soc. 2002, 124, 3292.
Angew. Chem., Int. Ed. 2002, 41, 2086.
Org. Lett., Vol. 11, No. 21, 2009
4787

before bromobenzene was added to react with unconverted
boronic acid ester functions.
Scheme 2. Synthesis of BINOL Building Block (M)-4
Scheme 4
.
Synthesis of Immobilized Bis(bipyridine) BINOL
M)-1
(
Scheme 3. Synthesis of Bis(bipyridine) BINOL (M)-6 and (M)-7
The gel was filtrated off and suspended in a 1:1 mixture
of THF and methanol containing a catalytic amount of
hydrochloric acid. After filtration, purification, and drying,
the light brown product was studied by infrared spectroscopy.
No boron-oxygen bands could be detected. To measure the
loading of the gel a C,H,N-elementary analysis was con-
ducted. Since the only source of nitrogen comes from the
chiral building block 7, the loading of the gel can be
(
M)-7 was then coupled with the boronated polystyrene
(
(
Scheme 4). For this a ratio of boronic acid ester groups to
M)-7 of 4:1 was used in order to get a moderate loading of
the chiral component on the gel. Although we also used THF,
because the swelling of the polystyrene beads is at a
maximum in this solvent, and aqueous potassium carbonate
solution as the base, we had to make several modifications
-
4
estimated by this method to be 5.37 × 10 mol/g of dried
gel. This translates to a yield of 49%.
Having achieved the immobilization of our bis(bipyridine)
BINOL ligand, we employed it for the chiral resolution of a
racemic mixture of a bis(bipyridine)-substituted derivative
1
3
compared to the protocol of Hodge and Zhang to immobilize
-bromo-1,1′-binaphthyl onto polystyrene to give credit to
of Tr o¨ ger’s base (8) (Figure 1) that could not be resolved
6
6
by HPLC on commercially available chiral stationary Whelk-
the bipyridines that can inactivate the palladium based
catalyst: we raised the amount of [Pd(PPh ] to 40 mol %.
Additionally, we used 10 mol % of tris(dibenzylidenacetone)-
dipalladium(0) chloroform adduct [Pd dba ·CHCl ] combined
with 30 mol % of tricyclohexylphosphane (PCy ) and 20
mol % of 1,1′-bis(diphenylphosphino)ferrocene (dppf) be-
cause the combination of [Pd dba ·CHCl ] and PCy has
proven to be remarkably active for Suzuki couplings and
the combination of the same Pd(0) source and dppf could
be demonstrated to be especially active in Sonogashira
reactions where bipyridines are involved, e.g., the synthesis
of 6. Furthermore, the reaction time was increased to 8 days
0
1 or DAICEL CHIRALPAK IA phases.
One enantiomer of this ligand 8 should interact stronger
3 4
)
with the (M)-1 and silver(I) ions because it should form the
more stable diastereomeric complex than the other enanti-
omer. Figure 1 depicts one possible complex that could be
formed when the (5R,11R)-enantiomer of the Tr o¨ ger’s base
ligand forms a dinuclear heteroleptic complex with the solid
supported (M)-configured BINOL ligand. In order to test this
hypothesis 1.5 g of (M)-1 was used to pack a column with
2
3
3
3
2
3
3
3
(
13) (a) Kiehne, U.; Weilandt, T.; L u¨ tzen, A. Org. Lett. 2007, 9, 1283.
(b) Kiehne, U.; Weilandt, T.; L u¨ tzen, A. Eur. J. Org. Chem. 2008, 2056.
4788
Org. Lett., Vol. 11, No. 21, 2009

+
at m/z 715.1 [Ag8] . It is very important to notice that when
we tried to use our immobilized ligand to resolve (rac)-8
without adding the silver(I) salt we only obtained one single
fraction of CD-silent (rac)-8, thus indicating that the resolu-
tion obtained with our immobilized ligand (M)-1 in the
presence of silver(I) ions indeed occurs via diastereoselective
self-assembly of heteroleptic complexes.
Figure 1. MMFF-minimized structure of the dinuclear silver(I)
complex of (5R,11R)-8 and (M)-1 (the polystyrene backbone is
indicated as a heptameric strand).
Figure 2
obtained from the chiral resolution of (rac)-8 on our chiral phase
M)-1.
. ECD spectra of fraction A (black) and fraction B (red)
a diameter of 1 cm and a height of 11 cm. Therefore, the
gel was suspended in a mixture of dichloromethane and
acetonitrile in a ratio of 3:1. After packing, swelling of the
beads, and washing was complete (no leakage of chiral
building blocks or low molecular polystyrene could be
detected), the mobile phase was switched to a 0.1 mol/L
solution of silver(I)tetrafluoroborate in dichloromethane/
acetonitrile 3:1. When the exchange of the mobile phase was
complete, 5 mg of the racemic ligand 8 dissolved in 200 µL
of dichloromethane/acetonitrile 3:1 was put on top of the
column, and cuts with a volume of 100 µL were collected.
After elution of 900 µL, the eluate became strongly yellow
colored, characteristic for a solution of a bipyridine silver(I)
complex. A 1.1 mL portion of this fraction (A) was collected
before the eluated solution began to pale again. After elution
of another 1.7 mL a second more intensively yellow colored
fraction (B) (1.9 mL) could be obtained. Both fractions A
(
In conclusion, we were able to synthesize a new enantio-
merically pure bis(bipyridine)BINOL ligand and immobilized
it on polystyrene beads in 18 overall steps. This can be used
as a chiral phase in the chiral resolution of a racemic mixture
of a similar bis(bipyridine) ligand based on a Tr o¨ ger’s base
derivative most probably by diastereoselective helicate
formation. After this proof of principle we are currently
trying to improve the performance of our approach in order
to establish it as a generic high-performance liquid chroma-
tography methodology for the resolution of other racemic
materials, e.g., by exploring other polymeric materials with
superior properties. Furthermore, we are also starting studies
to explore the potential of (M)-1 as a ligand for stereose-
lective reactions.
14
and B were then studied by ECD spectroscopy (see Figure
2
) and mass spectrometry.
As can be seen, the two fractions exert opposite Cotton
Acknowledgment. Financial support from the DFG (SFB
24) is gratefully acknowledged.
6
effects indicating a chiral enrichment of each enantiomer in
the two fractions. ESI-mass spectra of both fractions showed
a signal at m/z 411.0 as the base peak [Ag
Supporting Information Available: Synthetic schemes
and experimental and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
2
+
2
8] and a signal
(
14) Circular Dichroism: Principles and Applications; Berova, N.,
Nakanishi, K., Woody R. W., Eds.; Wiley-VCH: New York, 2000; p 877.
OL901958V
Org. Lett., Vol. 11, No. 21, 2009
4789