Enantioselective fluorescent recognition of a soluble "supported" chiral acid: Toward a new method for chiral catalyst screening

Article abstract of DOI:10.1021/ol0510163

(Chemical Equation Presented) The long-chain aliphatic-group-substituted mandelic acid 3c, which is soluble only in THF and insoluble in water and many polar/nonpolar organic solvents, has been synthesized. This unique solubility allows 3c to be easily is

Full text of DOI:10.1021/ol0510163

ORGANIC
LETTERS
2005
Vol. 7, No. 16
3441-3444
Enantioselective Fluorescent
Recognition of a Soluble “Supported”
Chiral Acid: Toward a New Method for
Chiral Catalyst Screening
Zi-Bo Li, Jing Lin, Ying-Chuan Qin, and Lin Pu*
Department of Chemistry, UniVersity of Virginia, CharlottesVille, Virginia 22904-4319
lp6n@Virginia.edu
Received May 3, 2005
ABSTRACT
The long-chain aliphatic-group-substituted mandelic acid 3c, which is soluble only in THF and insoluble in water and many polar/nonpolar
organic solvents, has been synthesized. This unique solubility allows 3c to be easily isolated from reaction mixtures and makes it potentially
useful for catalyst screening. The fluorescent sensors (R)- and (S)-1 can be used to determine the ees of various samples of 3c generated
from a series of catalyst screening experiments. The fluorescence measurements correlate well with the conventional HPLC-chiral column
analysis. This work demonstrates that the enantioselective fluorescent recognition of organic substrates can lead to a fundamentally new
method for chiral catalyst screening.
Development of analytical methods for high-throughput
chiral catalyst screening has attracted significant research
activity in recent years.1-6 Among these methods, the use
of fluorescence-based enantioselective sensors is particularly
interesting because fluorescence can potentially provide both
high sensitivity and real-time measurement.4 Work in this
area has led to various fluorescent sensors for the chiral
recognition of organic substrates in solution. For example,
we have found that the bisbinaphthyl macrocycles (S)- and
(R)-1 are highly enantioselective fluorescent sensors for
mandelic acid in solution.6
To conduct a high-throughput catalyst screening experi-
ment, it would be much more convenient to use a supported
substrate since this would allow an easy removal of the
catalysts and reagents and simplify the analysis of the
product. However, if a fluorescent sensor were used to
determine the enantiomeric composition of the product, it
would require a heterogeneous recognition of the supported
product, which is expected to be difficult because of the
nonspecific interaction with the surface of the supported
material. To apply the enantioselective fluorescent sensors
to the chiral catalyst screening, we have proposed to prepare
a substrate that would precipitate out of the catalyst screening
(1) Finn, M. G. Chirality 2002, 14, 534-540.
(2) Reetz, M. T. Angew. Chem., Int. Ed. 2002, 41, 1335-1338.
(3) Tsukamoto, M.; Kagan, H. B. AdV. Synth. Catal. 2002, 344, 453-
463.
(4) Pu, L. Chem. ReV. 2004, 104, 1687-1716.
(5) Mei, X.; Wolf, C. J. Am. Chem. Soc. 2004, 126, 14736-14737.
(6) Li, Z.-B.; Lin, J.; Pu, L. Angew. Chem., Int. Ed. 2005, 44, 1690-
1693.
10.1021/ol0510163 CCC: $30.25
© 2005 American Chemical Society
Published on Web 07/01/2005

Table 1. Solubility of Compounds 2a-c, 3a-c, and 5 in Various Solvents
reaction mixtures to allow simple separation but still be
soluble when used to interact with the fluorescent sensors.
Herein, we report our finding on the enantioselective
fluorescent recognition of a soluble “supported” mandelic
acid and its use in enantiomeric excess (ee) determination.
We are interested in developing chiral catalysts for the
conversion of the aldehyde 2 to the mandelic acid derivative
3 by various reaction pathways (Scheme 1). The following
4 was reacted with various linear alkyl bromides in order to
introduce alkyl groups to its benzene ring. It was found that
in 90% ethanol at reflux, the alkylation of the highly
functional 4 in the presence of KOH occurred with remark-
ably high selectivity at the phenol oxygen to give 3.
Table 1 summarizes the solubility of the aldehydes 2a-
c, the R-hydroxy acids 3a-c, and the ester 5. As the length
of the alkyl chain increases, the solubility of 3 in organic
solvents decreases. Compound 3c containing a 22-carbon
chain alkyl group is found to be almost insoluble in most of
the organic solvents but still has good solubility in THF. It
is also not soluble in water. This compound seems to have
all the desired solution properties. The corresponding alde-
hyde 2c is soluble in most organic solvents, which would
allow its reaction with other reagents to proceed homoge-
neously, and the product 3c would be precipitated out in the
absence of THF. The good solubility of 3c in THF will assist
its interaction with the fluorescent sensors (R)- and (S)-1,
which are soluble in many organic solvents, including THF.
The optically active samples of 3c were obtained by the
asymmetric reaction of 2c with TMSCN in methylene
chloride in the presence of Ti(OiPr)4 and (+)-/(-)-diisopro-
pyltartrate (DIPT) (70 mol %) at room temperature using a
modified literature procedure.7 The product was then treated
with HCl (g) and MeOH/Et2O (1:3) at room temperature,
which gave the methyl ester 5 (Scheme 3).8 The enantiomeric
Scheme 1. Asymmetric Conversion of Aldehydes to
R-Hydroxy Acids by Various Reaction Pathways
properties are desirable for compounds 2 and 3 when an
enantioselective fluorescent sensor is used to determine the
ee of 3 produced from the catalyst screening: (1) Compound
2 needs to be soluble in various solvents to allow the
conversion to be conducted in a homogeneous environment.
(2) After the conversion, 3 can be precipitated out with or
without the addition of a poor solvent. (3) Compound 3
should be soluble in a solvent or a mixture of solvents for
analysis by using a fluorescent sensor. (4) The fluorescent
sensors should show enantioselectivity in the recognition of
3.
Scheme 3. Asymmetric Reaction of 2c with TMSCN in the
Presence of (+)-/(-)-DIPT and Ti(OiPr)4 to Generate 5 and 3c
Introduction of a nonpolar aliphatic group to the benzene
ring of the highly polar mandelic acid was examined with
the expectation that the combination of such distinctively
different molecular fragments together should lead to inter-
esting solution properties. As shown in Scheme 2, compound
Scheme 2. Synthesis of Alkylated 4-Hydroxy Mandelic Acid
purity of 5 was determined using an HPLC-chiral OD
column. The ester (S)-5, obtained by using (+)-DIPT, was
produced with 79.5% ee (that is, 90% (S)-enantiomer), and
(R)-5, obtained by using (-)-DIPT, was produced with 72%
3442
Org. Lett., Vol. 7, No. 16, 2005

ee (that is, 86% (R)-enantiomer). Compound 5 was converted
to 3c by treatment with KOH in dioxane at 60 °C, which
precipitated out with acidification. To determine if the
hydrolysis condition could racemize the chiral center of 3c,
we converted 3c back to 5 by reaction with HCl (g) and
MeOH/Et2O (1:3). HPLC analysis of 5 showed a slight
increase in ee (∼3.5%). This demonstrates that no racem-
ization took place during the hydrolysis of 5 to 3c.
On the basis of the interaction of the enantiomeric sensors
(R)- and (S)-1 with 3c of various enantiomeric compositions,
a linear relationship between the fluorescence intensity
difference ∆I [∆I ) (IS/IS0) - (IR/IR0); IS, fluorescence
intensity of (S)-1 in the presence of the acid; IR, fluorescence
intensity of (R)-1 in the presence of the acid; IS0 and IR0,
fluorescence intensity of (R)-/(S)-1 without the acid] and the
ee of 3c is established (Figure 3). Thus, using Figure 3, one
The optically active (R)- and (S)-3c obtained above were
allowed to interact with the fluorescent sensors (S)- and (R)-
1. We found that in a ternary solvent of THF/hexane/benzene
(1:5.5:18.5), the sensors (2.0 × 10-5 M) showed enantio-
selective fluorescent responses to the chiral acids (2.0 × 10-4
M) (Figure 1). THF was used to dissolve 3c, and the
Figure 3. Relationship between ∆I and the enantiomeric composi-
tion of mandelic acid.
Figure 1. Fluorescence spectra of (R)-1 (2.0 × 10-5 M) with (R)-
and (S)-3c (2.0 × 10-4 M) (λexc ) 332 nm, slit ) 3.5; 6.5 nm).
should be able to determine the enantiomeric composition
of a given sample of 3c from ∆I.
We studied the conversion of 2c to 3c by the TMSCN
addition in the presence of the chiral ligands (S)-/(R)-69 and
(+)-/(-)-DIPT in combination with Ti(OiPr)4 under various
conditions as summarized in Table 2. The product 3c was
combination of benzene and hexane was necessary for the
enantioselective fluorescent response. Although the enantio-
selectivity of the sensor for 3c is significantly lower than
that for the unsubstituted mandelic acid, it is still useful for
ee determination (vide infra).6
Samples of 3c (2.0 × 10-4 M) with various enantiomeric
compositions were prepared, and their interaction with (R)-1
(2.0 × 10-5 M) in the ternary solvent system was studied.
A monotonic relation between the fluorescence intensity and
the enantiomeric composition of the acid was obtained
(Figure 2). We also studied the interaction of the samples
with (S)-1 and observed a mirror image relationship for the
fluorescence responses. This confirmed the observed chiral
recognition of 3c by the fluorescent sensor.
Table 2. Asymmetric TMSCN Addition to 2c and Fluorescent
Ee Determination of Product 3c
ligand
(mol %)
Ti(OiPr)4
(mol %) (IS/IS0 - IR/IR0
∆I )
ee
(%)
entry solvent
)
1
2
3
4
5
6
7
8
9
CH2Cl2 (+)-DIPT (40)
CH2Cl2 (-)-DIPT (40)
CH2Cl2 (S)-6 (10)
CH2Cl2 (S)-6 (10)
CH2Cl2 (S)-6 (10)
40
40
8
10
12
10
10
10
10
2
1.92
-1.81
2.06
1.33
0.38
0.99
0.11
0.95
-1.26
-1.31
79
-77
84
54
14
39
3
38
-54
-56
THF
ether
(S)-6 (10)
(S)-6 (10)
toluene (S)-6 (10)
CH2Cl2 (R)-6 (10)
CH2Cl2 (R)-6 (10)
10
isolated in the range of 60-70% yield simply by centrifuga-
tion and filtration because of the insolubility of 3c in the
absence of THF. The 10 samples of 3c obtained from the
above catalyst screening were treated with the fluorescent
(7) Hayashi, M.; Matsuda, T.; Oguni, N. J. Chem. Soc., Perkin Trans. 1
1992, 22, 3135-3140. For the modification, see Supporting Information.
(8) Tanaka, K.; Mori, A.; Inoue, S. J. Org. Chem. 1990, 55, 181-185.
(9) Li, Z.-B.; Rajaram, A. R.; Decharin, N.; Qin, Y.-C.; Pu, L.
Tetrahedron Lett. 2005, 46, 2223-2226.
Figure 2. Fluorescence responses of (R)-1 (2.0 × 10-5 M) with
3c (2.0 × 10-4 M) at various R compositions (λexc ) 332 nm, slit
) 3.5; 6.5 nm).
Org. Lett., Vol. 7, No. 16, 2005
3443

sensors (R)- and (S)-1 under the same conditions as those in
Figure 2. The ees of the samples were determined according
to Figure 3 by measuring ∆I.
We also used an HPLC-chiral OD column to analyze the
ees of the methyl esters 5 obtained from the screening
experiments in Table 2. Table 3 compares the HPLC data
Table 3. Comparison of the Ees from HPLC Analysis with
Those from Fluorescence Measurements
sample
1
2
3
4
5
6
7
8
9
10
FL
HPLC
79 -77 84 54 14 39
73 -69 72 49 23 50
3
8
38 -54 -56
44 -47 -54
isolated from a reaction mixture and makes it potentially
useful for catalyst screening. We have demonstrated that the
fluorescent sensors (R)- and (S)-1 can be used to determine
the ees of 3c generated from a series of catalyst screening
experiments. The fluorescence measurements correlate well
with the conventional HPLC-chiral column analysis. This
work demonstrates that the enantioselective fluorescent
recognition of organic substrates may open the door to a
fundamentally new method for chiral catalyst screening.
Acknowledgment. We thank the National Institutes of
Health for partial support of this research (R01GM58454/
R01EB002037).
with those from the fluorescence measurements, and a good
correlation is observed.
In summary, we have synthesized the long-chain aliphatic-
group-substituted mandelic acid 3c, which is soluble only
in THF and insoluble in water and many polar/nonpolar
organic solvents. This unique solubility allows 3c to be easily
Supporting Information Available: Syntheses and char-
acterizations of the new compounds and details of the
fluorescence measurements. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL0510163
3444
Org. Lett., Vol. 7, No. 16, 2005