Efficient NMR Enantiodifferentiation of Chiral Quats with BINPHAT Anion

Article abstract of DOI:10.1021/ol025669k

(Matrix Presented) Hexacoordinated phosphorus BINPHAT anion is an efficient NMR chiral shift agent for quaternary ammonium cations (quats) leading to large separations (ΔΔδ up to 0.29 ppm) of the proton signals of the enantiomers.

Full text of DOI:10.1021/ol025669k

ORGANIC
LETTERS
2002
Vol. 4, No. 8
1351-1354
Efficient NMR Enantiodifferentiation of
Chiral Quats with BINPHAT Anion
Je´roˆme Lacour,* Laurent Vial, and Christelle Herse
De´partement de Chimie Organique, UniVersite´ de Gene`Ve, quai Ernest-Ansermet 30,
CH-1211 Gene`Ve 4, Switzerland
jerome.lacour@chiorg.unige.ch
Received February 5, 2002
ABSTRACT
Hexacoordinated phosphorus BINPHAT anion is an efficient NMR chiral shift agent for quaternary ammonium cations (quats) leading to large
separations (∆∆δ up to 0.29 ppm) of the proton signals of the enantiomers.
Chiral quaternary ammonium cations or quats have been the
subject of much attention due to the potential of these
derivatives to serve as efficient chiral phase transfer cata-
lysts.1 Whereas most examples of highly stereoselective
reactions have employed cations derived from the chiral
pool2sfor which the enantiomeric purity is ascertaineds
recent reports of successful transformations mediated by
purely synthetic chiral quats, e.g., 1 (Figure 1),3 raises the
artificial receptors with the goal to develop a better under-
standing of the biologically important cation-π inter-
actions.5,6 In several of these reports, the aromatic hosts have
been chiral.7 It is therefore conceivable that stereoselective
(1) Nelson, A. Angew. Chem., Int. Ed. 1999, 38, 1583-1585.
(2) Dolling, U. H.; Davis, P.; Grabowski, E. J. J. J. Am. Chem. Soc.
1984, 106, 446-447. Zhang, F.; Corey, E. J. Org. Lett. 2001, 3, 639-641.
Corey, E. J.; Zhang, F.-Y. Angew. Chem., Int. Ed. 1999, 38, 1931-1934.
Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414-
12415. Lygo, B.; Crosby, J.; Peterson, J. A. Tetrahedron 2001, 57, 6447-
6453. Lygo, B.; Crosby, J.; Lowdon, T. R.; Peterson, J. A.; Wainwright, P.
G. Tetrahedron 2001, 57, 2403-2409 and references therein.
(3) Ooi, T.; Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 1999, 121,
6519-6520. Ooi, T.; Takeuchi, M.; Kameda, M.; Maruoka, K. J. Am. Chem.
Soc. 2000, 122, 5228-5229. Ooi, T.; Doda, K.; Maruoka, K. Org. Lett.
2001, 3, 1273-1276.
(4) This is not the case for cations of type 1; the enantiomeric purity is
directly correlated to the BINOL starting material.
(5) Lehn, J.-M. Supramolecular Chemistry. Concepts and PerspectiVes;
VCH Verlaggesellschaft: Weinheim, 1995.
(6) Ma, J. C.; Dougherty, D. A. Chem. ReV. 1997, 97, 1303-1324.
(7) (a) Kubik, S.; Goddard, R. Eur. J. Org. Chem. 2001, 311-322. (b)
Kubik, S. J. Am. Chem. Soc. 1999, 121, 5846-5855. (c) Vysotsky, M. O.;
Pop, A.; Broda, F.; Thondorf, I.; Bo¨hmer, V. Chem. Eur. J. 2001, 7, 4403-
4410. (d) Rebek, J. Chem. Commun. 2000, 637-643. (e) Terpin, A. J.;
Ziegler, M.; Johnson, D. W.; Raymond, K. N. Angew. Chem., Int. Ed. 2001,
40, 157-160, (f) Cousins, G. R. L.; Furlan, R. L. E.; Ng, Y. F.; Redman,
J. E.; Sanders, J. K. M. Angew. Chem., Int. Ed. 2001, 40, 423-428. (g)
Kirchhoff, P. D.; Dutasta, J.-P.; Collet, A.; McCammon, J. A. J. Am. Chem.
Soc. 1999, 121, 381-390. (h) Meric, R.; Vigneron, J. P.; Lehn, J. M. J.
Chem. Soc., Chem. Commun. 1993, 129-131. (i) Morozumi, T.; Shinkai,
S. J. Chem. Soc., Chem. Commun. 1994, 1219-1220. (j) Konishi, H.;
Figure 1. Quaternary ammonium cations (quats) 1-3.
general question of the determination of the enantiomeric
purity of such synthetic derivatives.4
Quats, such as acetylcholine 2 (Figure 1), have also been
recently studied for their binding with aromatic natural and
10.1021/ol025669k CCC: $22.00 © 2002 American Chemical Society
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discriminating interactions could occur between them and
chiral quats such as biologically active methacholine 3.7i-l
It appeared to us that such studies would strongly benefit
from the use of salts in which the two enantiomers of the
chiral quaternary ammonium cations could be directly
Chiral quats 4-8 were prepared as racematesswhen possible
in enantiopure formsby the reaction of the amine precursors
with an excess of MeI/NaHCO3 in MeOH, affording chemi-
cally pure starting materials in moderate to good yields (42-
98%). Racemic methacholine 3 was commercially available
as its bromide salt.
1
detected in H NMR spectroscopy as titration experiments
could be performed with racemic quats for which the pure
Recently, chiral hexacoordinated phosphate anions, BIN-
PHAT 9 (bis(tetrachlorobenzenediolato)mono([1,1′]binaph-
thalenyl-2,2′-diolato)phosphate(V)), TRISPHAT 10 (tris-
(tetrachlorobenzenediolato)phosphate(V)), and HYPHAT 11
(bis(tetrachlorobenzenediolato)mono(1,2-diphenylethane-1,2-
diolato)phosphate(V)), were shown to be readily prepared
in one or two steps from commercially available starting
materials (Figure 3).10 These diamagnetic anions are efficient
enantiomers are not readily available.8
Herein, we report that the ion pairing of chiral quaternary
ammonium cations and recently developed BINPHAT (Fig-
ure 3) allows the strong enantiodifferentiation of the proton
NMR signals of the ammonium cations; rather large differ-
ence in chemical shifts (∆∆δ)sup to 0.29 ppmswere
observed upon asymmetric ion pairing. This allows for the
efficient determination of the enantiomeric purity of chiral
quats.9
Several chiral quaternary ammonium cations (4-8) were
chosen along with methacholine 3 (Figure 2). Care was taken
Figure 3. Chiral phosphate anions BINPHAT 9, TRISPHAT 10,
and HYPHAT 11.
NMR chiral shift agents, with a predilection for cationic
metallo-organic and organo-metallic substrates.11 The ef-
ficiency of the anions is explained by the formation of
diastereomeric contact ion pairs. In most of the studies, the
chiral shift experiments were performed by the addition of
[Bu3NH][Λ-10] or [Bu4N][∆-10] to solutions of the chiral
cations.11 However, recent results have shown that C2-
symmetric BINPHAT 9 and HYPHAT 11 anions often
possess better chiral shift properties than TRISPHAT 10
when associated with organic cations.10b,12
Figure 2. Chiral quaternary ammonium cations 3-8 and magnitude
of the difference in chemical shifts (∆∆δ in small figures) for well-
separated signals of the BINPHAT salts.
to select rather different backbones with stereogenic center-
(s) in R and/or â positions to the positive nitrogen atom.
Tamura, T.; Okhkubo, H.; Kobayashi, K.; Morikawa, O. Chem. Lett. 1996,
685-686. (k) Ito, K.; Kida, A.; Ohba, Y.; Sone, T. Chem. Lett. 1998, 1221-
1222. (l) Ito, K.; Ohta, T.; Ohba, Y.; Sone, T. J. Heterocycl. Chem. 2000,
37, 79-85 and references therein.
Initial experiments were performed with racemic trimethyl-
(1-phenylethyl)ammonium iodide salt. In an NMR tube,
(8) A modest split (∆∆δ < 0.015) was observed by Ito for cation rac-4
in the presence of modified calixarene hosts: refs 7k and 7l.
(9) In situ generated anionic lanthanide complexes have been used as
chiral shift reagents onto chiral cations. However, to our knowledge, their
use on quaternary ammonium derivatives has not been reported: Vining,
M. S.; Weinstein, S. E.; Wenzel, T. J. In Book of Abstracts, 216th National
Meeting of the American Chemical Society, Boston, August 23-27, 1998;
American Chemical Society: Washington, DC, 1998; Abstract ANYL-124.
Green, T. K.; Pesterfield, L. L.; Radmard, B.; Whetstine, J. R. Magn. Reson.
Chem. 1998, 36, 79-86. Green, T. K.; Whetstine, J. R.; Son, E. J. R.
Tetrahedron: Asymmetry 1997, 8, 3175-3181. Wenzel, T. J.; Zaia, J. Anal.
Chem. 1987, 59, 562-567.
(10) (a) Lacour, J.; Ginglinger, C.; Grivet, C.; Bernardinelli, G. Angew.
Chem., Int. Ed. Engl. 1997, 36, 608-609. (b) Lacour, J.; Londez, A.;
Goujon-Ginglinger, C.; Buss, V.; Bernardinelli, G. Org. Lett. 2000, 2, 4185-
4188. (c) Lacour, J.; Londez, A. J. Organomet. Chem. 2002, 643-644,
392-403.
(11) Lacour, J.; Ginglinger, C.; Favarger, F.; Torche-Haldimann, S. Chem.
Commun. 1997, 2285-2286. Ratni, H.; Jodry, J. J.; Lacour, J.; Ku¨ndig, E.
P. Organometallics 2000, 19, 3997-3999. Jodry, J. J.; Lacour, J. Chem.
Eur. J. 2000, 6, 4297-4304.
(12) Pasquini, C.; Desvergnes-Breuil, V.; Jodry, J. J.; Dalla Cort, A.;
Lacour, J. Tetrahedron Lett. 2002, 43, 423-426.
1352
Org. Lett., Vol. 4, No. 8, 2002

[nBu4N][(∆,S)-9]13 was added to a CDCl3 solution of [rac-
4][I] (Figure 4). Although efficient (∆δ ) 0.13 ppm), the
solutions of [Me2NH2][(∆,S)-9] (1.2 equiv) in acetone and
of 5.0 mg of salts [3][Br] or [4-8][I] in CH2Cl2 were
prepared and mixed together. Aliquots were adsorbed on
basic alumina (5 × 30 mm, Pasteur pipet) and eluted with a
few milliliters of CH2Cl2 (∼5 mL) to afford salts [3-8]-
[(∆,S)-9] as the only eluted compounds.15
BINPHAT salts of trimethyl(1-phenylethyl)ammonium 4
were thus prepared with the racemic, the R, the S, and an
undetermined mixture of the enantiomers of the cation. Parts
of the NMR spectra are shown in Figure 5 and are compared
to the iodide salt (spectrum a). All aliphatic protons were
easily monitored; observed chemical shifts (δ), upfield shifts
induced by the phosphate anion (∆δ), and the magnitude of
the difference in chemical shifts (∆∆δ) of analogous protons
of the two enantiomers of 4 are summarized in Table 1. A
Table 1. Chemical Shifts (δ), Induced Changes (∆δ), and
Magnitude of the Changes (∆∆δ) for Salts [rac-4][I],
[R-4][(∆,S)-9], and [S-4][(∆,S)-9] (CDCl3, 400 MHz)
Figure 4. 1H NMR spectra (400 MHz, CDCl3, parts) of [rac-4][I]
with (a) 0, (b) 0.5, (c) 1.5, and (d) 4.8 equiv of [nBu4N][(∆,S)-9].
proton
δa
δb
δc
∆δb
∆δc
∆∆δ
separation of the signals of the benzilic proton of 4 could
only be achieved with a substantial amount of chiral shift
salt (4.8 equiv), and a rather large spectral window was
perturbed in the aliphatic region (2.93-0.54 ppm) by the
protons of the tetra-n-butylammonium counterion. While this
was acceptable for this particular example, strong overlapss
which would prevent any measurementsswere foreseen to
happen with chiral cations depleted of signals outside this
region, e.g., 6-7. The direct association of cations 3-8 and
anionic chiral shift agent 9 in preformed [3-8][(∆,S)-9] salts
was thus considered to be a better solution, as a much larger
spectral window would be available.
CHMe
N(Me)3
CHMe
5.40
3.38
1.85
4.38
2.36
1.09
4.22
2.46
1.15
-1.02
-1.02
-0.76
-1.18
-0.92
-0.70
0.16
-0.10
-0.06
a [rac-4][I]. b [R-4][(∆,S)-9]. c [S-4][(∆,S)-9].
rather large difference in chemical shifts (∆∆δmax ∼0.16
ppm) was observed for the benzylic proton, allowingsfor
the enantioenriched samplesthe facile determination of its
enantiomeric purity by integration of the respective signals
(Figure 5, spectrum e, er 78:22 in favor of R-4). To ensure
that BINPHAT anion was indeed the best anionic chiral shift
agent, salts [rac-4][(S,S)-11] and [rac-4][∆-10] were prepared
(Figure 5, spectra f and g). Little or no separation of the
signals of cation 4 was obtained with these anions, validating
the initial choice.
Recently, we observed that hexacoordinated phosphate
anions 9-11 confer to their salts a poor affinity for polar
chromatographic phases as they elute rapidly over silica gel/
alumina.14 For the preparation of salts [3-8][(∆,S)-9],
Figure 5. 1H NMR spectra (400 MHz, CDCl3, parts) of (a) [rac-4][I], (b) [rac-4][(∆,S)-9], (c) [R-4][(∆,S)-9], (d) [S-4][(∆,S)-9], (e)
[R-4][(∆,S)-9] (er 78:22), (f) [rac-4][(S,S)-11], and (g) [rac-4][∆-10].
Org. Lett., Vol. 4, No. 8, 2002
1353

With cation 5, upfield shifts induced by the phosphate
reagent and large differences in chemical shifts for the
analogous protons of the two enantiomers were also observed
(Figures 3 and 6). The signals of the N+Me3 protons (∆∆δ
of aromatic substituents. For salt [rac-7][(∆,S)-9], the overall
spectrum was complex. Nevertheless, the methyl group â to
the charged nitrogen atom was sufficiently split by the chiral
counterion (baseline-to-baseline separation, ∆∆δ ) 0.15
ppm) and the lack of overlap with other signals would
allowsif necessarysa possible determination of the enan-
tiomeric purity. For compound 8, more polar solvent condi-
tions for the preparation, the elution, and the final charac-
terization of [rac-8][(∆,S)-9] salt were required. Splits of
the N-Me signal and, more interestingly, of the OH proton
(∆∆δ ) 0.11 ppm, see Supporting Information) were
observed, with the rest of the spectrum being complex.
Interestingly, this methodology could also be applied for
biologically active methacholine 3 as the two enantiomers
of the cation could be easily observed upon ion pairing with
9; signals N+Me3 and CHMe (∆∆δ ) 0.06 and 0.24 ppm,
respectively) were the most separated. The methyl group of
the acetate moietysalthough positioned ꢀ to the charged
nitrogen atomswas slightly split by the chiral shift anion
(∆∆δ ) 0.01 ppm, Supporting Information).
Since a purification step is involved in this protocol, care
was and should be taken to verify that this method does not
lead to any resolution of the ammonium cations upon
chromatography, as one of the two diastereomeric BINPHAT
ion pairs could be more retained over Al2O3. Further studies
on the interaction of these BINPHAT salts and chiral
aromatic receptors are currently in progress.
Figure 6. 1H NMR spectra (400 MHz, CDCl3, parts) of (a) [rac-
5][I], (b) [rac-5][(∆,S)-9], and (c) [(R,R)-5][(∆,S)-9].
) 0.25 ppm) were the most perturbed. For sec-butyltri-
methylammonium cation 6, several signals of the ammonium
cation were fully split upon the association with 9 (Figure 2
(∆∆δ) and Supporting Information). Interestingly, the most
shifted signals are those of the methyl group positioned γ to
the charged nitrogen atom (∆∆δ ) 0.29 ppm) and not R or
â (∆∆δ ) 0.06 ppm). This example and the next (cation 7,
see Supporting Information) clearly indicate that the ef-
ficiency of the BINPHAT anion is not tempered by the lack
Acknowledgment. We thank Dr. Klaus Ditrich (BASF)
for a generous gift of R- and S-1-phenylethylamine. We are
grateful for financial support of this work by the Swiss
National Science Foundation, the Federal Office for Educa-
tion and Science (COST D11), the Socie´te´ Acade´mique de
Gene`ve, the Schmidheiny Foundation, and the Fondation de
Famille Sandoz.
(13) Reagent [nBu4N][(∆,S)-9] was prepared by metathesis from [Me2-
NH2][(∆,S)-9] and [nBu4N][Cl]. Salt [Me2NH2][9], and the resulting [Me2-
NH2][Cl] are completely retained on Al2O3 using CH2Cl2 as eluent.
(14) Lacour, J.; Barche´chath, S.; Jodry, J. J.; Ginglinger, C. Tetrahedron
Lett. 1998, 39, 567-570. Monchaud, D.; Lacour, J.; Coudret, C.; Fraysse,
S. J. Organomet. Chem. 2001, 624, 388-391 and ref b.
Supporting Information Available: Preparation and
1
spectral data for salts [4-8][I] and [nBu4N][(∆,S)-9]. H
NMR spectra of compounds [3-8][(∆,S)-9]. This material
is available free of charge via the Internet at http://pubs.acs.org.
(15) For salt [8][I], a minimum amount of MeOH was required to dissolve
it in CH2Cl2; 5% acetone in CH2Cl2 was required for its elution on Al2O3.
OL025669K
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Org. Lett., Vol. 4, No. 8, 2002