A new hydrogen-bonding motif for chiral recognition in the diastereomeric salts of racemic 1-phenylethylamine derivatives with enantiopure O-ethyl phenylphosphonothioic acid

Article abstract of DOI:10.1021/ol0483145

(Chemical Equation Presented) An enantiopure phosphonothioic acid showed a unique and superior chiral recognition ability, arising from its P-stereogenicity, for racemic 1-phenylethylamine derivatives through diastereomeric crystallization. Spherical molecular clusters, associated by hydrogen bonds and CH/π interactions, aggregated with high symmetry in the less-soluble diastereomeric salts.

Full text of DOI:10.1021/ol0483145

ORGANIC
LETTERS
2004
Vol. 6, No. 23
4227-4230
A New Hydrogen-Bonding Motif for
Chiral Recognition in the Diastereomeric
Salts of Racemic 1-Phenylethylamine
Derivatives with Enantiopure O-Ethyl
Phenylphosphonothioic Acid
Yuka Kobayashi, Fumi Morisawa, and Kazuhiko Saigo*
Department of Chemistry and Biotechnology, Graduate School of Engineering,
The UniVersity of Tokyo, Hongo, Bunkyo-ku, Tokyo, 113-8656, Japan
saigo@chiral.t.u-tokyo.ac.jp
Received August 24, 2004
ABSTRACT
An enantiopure phosphonothioic acid showed a unique and superior chiral recognition ability, arising from its P-stereogenicity, for racemic
1-phenylethylamine derivatives through diastereomeric crystallization. Spherical molecular clusters, associated by hydrogen bonds and CH/
π
interactions, aggregated with high symmetry in the less-soluble diastereomeric salts.
Compounds containing chiral phosphorus atom(s) (P-chiral)
have been attracting great interest in organic chemistry;
enantiopure P-chiral phosphinothioic acids and phosphines
are particularly known to be useful as solvating agents for
the determination of enantiomeric excesses1 and ligands for
transition metal catalysts,2 respectively. Moreover, in the field
of biochemistry, the synthesis and application of enantiopure
P-chiral nucleotide, DNA, and RNA analogues are hot
topics.3
O-Substituted phosphonothioic acids, a series of P-chiral
compounds, are stable Brønsted acids as carboxylic acids,
sulfonic acids, and phosphonic acids. However, from the
viewpoint of structural features, O-substituted phosphono-
thioic acids are quite different from the other organic
Brønsted acids. The acidic functional group of O-substituted
phosphonothioic acids is chiral, whereas those of the other
organic Brønsted acids are achiral; the phosphorus atom in
O-substituted phosphonothioic acids is not only an element
of an acidic functional group but also a chiral center, as
shown in Figure 1. This structural characteristic of O-
substituted phosphonothioic acids suggests that enantiopure
O-substituted phosphonothioic acids would be able to offer
a rigorously controlled, three-dimensionally dissymmetric
environment when the acidic functional group interacts with
a substrate. Moreover, different from the acidic functional
(1) (a) Harger, M. J. P. J. Chem. Soc., Perkin Trans. 2 1978, 326-331.
(b) Moriyama, M. W.; Bentrude, G. J. Am. Chem. Soc. 1983, 105, 4727-
4733. (c) Bentrude, W. G.; Moriyama, M.; Mueller, H.-D.; Sopchik, A. E.
J. Am. Chem. Soc. 1983, 105, 6053-6061. (d) Drabowicz, J.; Dudzinski,
B.; Mikolajczyk, M. Tetrahedron: Asymmetry 1992, 3, 1231-1234. (e)
Omelanczuk, J.; Mikolajczyk, M. Tetrahedron: Asymmetry 1996, 7, 2687-
2694. (f) Drabowicz, J.; Dudzinski, B.; Mikolajczyk, M. St. Colonna;
Gaggero, N. Tetrahedron: Asymmetry 1997, 8, 2267-2270.
(2) (a) Kagan, H. B.; Sasaki, M. In Chemistry of Organophosphorus
Compounds; Hartley, F. R., Ed.; Wiley & Sons: New York, 1990; Vol. 1,
Chapter 3. (b) Imamoto, T. In Handbook of Organophosphorus Chemistry;
Engel, R., Ed.; Marcel Dekker: New York, 1992; Chapter 1.
(3) Yu, D.; Kandimalla, E. R.; Roskey, A.; Zhao, Q.; Chen, J.; Agrawal,
S. Bioorg. Med. Chem. 2000, 8, 275-284.
10.1021/ol0483145 CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/21/2004

Table 1. Enantioseparation of 1-Phenylethylamine Derivatives
2 with (Sp)-1
amine
R
yield (%)a
ee (%)b efficiencyc abs configd
2a
2b
2c
2d
2e
2f
H
o-Me
78
not crystallized
m-Me not crystallized
p-Me 52
p-OMe 45
98
0.76
R
Figure 1.
>99
>99
96
>99
95
0.51
0.45
0.81
0.83
0.79
R
S
R
R
R
groups of carboxylic acids, sulfonic acids, and phosphonic
acids, the acidic functional group of O-substituted phospho-
nothioic acids can give two obviously different hydrogen-
accepting sites, sulfur and oxygen atoms, upon transforming
them into the corresponding anionic forms by interaction with
a basic substrate. Although enantiopure O-substituted phospho-
nothioic acids have such distinct characteristics, only frag-
mented reports appear on their enantio-differenciating sol-
vation ability4 and biological activity.5a These facts prompted
us to apply O-substituted phosphonothioic acids with unique
stereogenicity to the enantioseparation of racemates as new
resolving agents. We report here the chiral recognition ability
of an enantiopure O-alkyl phosphonothioic acid in the
enantioseparation of racemic 1-phenyletylamine derivatives
by diastereomeric salt formation and a new hydrogen-
bonding motif for the chiral recognition.
p-F
p-Cl
p-Br
84
84
83
2g
2h
a Yield of the crystallized diastereomeric salt based on a half amount of
the racemic amine. b Enantiomeric excess (ee) of the liberated amine, which
was determined by HPLC analysis. c Efficiency is the product of the yield
and the ee. d Absolute configration of the major enantiomer, which was
determined by a X-ray crystallographic analysis and/or deduced on the basis
of the elution order in the HPLC analysis.
of 1-phenylethylamine derivatives 2; once the salt crystals
could deposit, (Sp)-1 recognized the stereogenicity of 2 with
excellent selectivity. Especially in the enantioseparations of
2d, 2e, and 2g, the corresponding enantiopure amines were
obtained by only single crystallization.
In the next stage, the X-ray crystallographic analyses of
the less-soluble diastereomeric salts were carried out in order
to extract the factors leading to such an excellent chiral
recognition ability of (Sp)-1. Among six combinations of
1-phenylethylamine derivatives and (Sp)-1 we succeeded in
enantioseparating, the less-soluble diastereomeric salts of 2a,
2d, 2g, and 2h with (Sp)-1 satisfactorily gave single crystals
suitable for X-ray crystallographic analyses. All of the four
less-soluble diastereomeric salt crystals have the same crystal
system of tetragonal, and the space group is P43212 with
high symmetry, which is very rare for such organic salt
crystals. Figures 2 and 3 show a typical example ((Sp)-1‚
(R)-2d) of the crystal structures of the less-soluble diaster-
eomeric salts.8 In the crystal, four molecules of (Sp)-1 and
four molecules of (R)-2d form a spherical cluster with a
pseudo-two-fold axis, in which a hydrophilic core consisting
of a hydrogen-bonding network is surrounded by the
hydrophobic alkyl and aryl groups of (Sp)-1 and (R)-2d. The
hydrogen-bonding network is composed of hydrogen bonds
not only between the nitrogen atom in (R)-2d and the oxygen
atom in (Sp)-1 but also between the nitrogen atom in (R)-2d
and the sulfur atom in (Sp)-1. The characteristic spherical
cluster makes the crystal highly symmetrical as tetragonal.
The crystal of (Sp)-1‚(R)-2d is consequently built up from
the spherical clusters, which interact with each other by CH/π
and van der Waals interactions along a two-fold screw axis.
As an enantiopure O-substituted phosphonothioic acid, we
chose O-ethyl phenylphosphonothioic acid (1) because the
synthesis and enantioseparation of 1 have been reported.5
Starting from commercially available phenylphosphonothioic
dichloride, racemic O-ethyl phenylphosphonothioic acid was
easily synthesized in 91% total yield via two steps, and
enantiopure (Sp)-O-ethyl phenylphosphonothioic acid ((Sp)-
1) was successfully obtained by the enantioseparation of the
racemate with (R)-1-phenylethylamine.6
To clarify the chiral recognition ability of (Sp)-1, we at
first carried out the enantioseparation of systematically
selected 1-phenylethylamine derivatives by using (Sp)-1 as
a resolving agent.7 As can be seen from Table 1, (Sp)-1
showed a very unique chiral recognition ability with a series
(4) (a) Mikolajczyk, M.; Omelanczuk, J. Tetrahedron Lett. 1972, 16,
1539-1541. (b) Mikolajczyk, M.; Omelanczuk, J.; Leitloff, M.; Drabowicz,
J.; Ejchart, A.; Jurczak, J. J. Am. Chem. Soc. 1978, 100, 7003-7008.
(5) (a) Lu, H.; Berkman, C. E. Bioorg. Med. Chem. 2001, 9, 395-402.
(b) Allahyari, R.; Lee, P. W.; Lin, G. H. Y.; Wing R. M.; Fukuto, T. R. J.
Agric. Food Chem. 1977, 25, 471-478. (c) Allahyari, R.; Hollingshaus, J.
G.; Lapp, R. L.; Timm, E.; Jacobson, R. A.; Fukuto, T. R. J. Agric. Food
Chem. 1980, 28, 594-599. (d) Lewis, V. E.; Donarski, W. J.; Wild, J. R.;
Raushel, F. M. Biochemistry 1988, 27, 1591-1597.
(6) For details of the synthesis and enantioseparation of racemic O-ethyl
phenylphosphonothioic acid, see Supporting Information. In a similar
manner, several kinds of enantiopure O-substituted phosphonothioic acids
could be prepared. The application of the phosphonothioic acids as resolving
agents is now in progress.
(7) The enantioseparations were carried out under almost the same
conditions. The diastereomeric salt was crystallized from stirred ether/hexane
at room temperature. The amount and ratio of the mixed solvent were
adjusted to control the yield of the precipitated salt as close as possible
within 50-80%.
(8) Crystal data for the less-soluble (S)-1‚(R)-2d: FW ) 337.42,
tetragonal, space group P43212, a ) 13.6603(9), b ) 13.6603(9), c )
40.7660(4) (Å), V ) 7607.1(10) Å3, Z ) 16, R ) 0.0660, Rw ) 0.0710.
For preliminary data for the other crystals, see Supporting Information.
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Org. Lett., Vol. 6, No. 23, 2004

Figure 2. Hydrogen bonds and CH/π interactions in the spherical
cluster of the less-soluble (Sp)-1‚(R)-2d. The black and red dashed
lines indicate hydrogen bonds and CH/π interactions, respectively.
The values are the distances of the hydrogen bonds in angstroms.
The pseudo-two-fold axis is not identical with the c axis.
The formation of a spherical cluster from four molecules of
(Sp)-1 and four molecules of an amine and the aggregation
of the clusters by CH/π and van der Waals interactions were
commonly observed in the crystals of the other less-soluble
diastereomeric salts (Sp)-1‚(R)-2a, (Sp)-1‚(R)-2g, and (Sp)-
1‚(R)-2h. Such a closed hydrogen-bonding network is
entirely unpredictable from the crystal structures of the less-
soluble diastereomeric salts derived from conventional
resolving agents; the less-soluble diastereomeric salt crystals
commonly consist of an infinite columnar or sheetlike
hydrogen-bonding network.9 The formation of such a closed
hydrogen-bonding motif in a chiral recognition phenomenon
is the first example as far as we know.10 The spherical cluster
formation would arise from the structural characteristic of
(Sp)-1 that the phosphorus atom of the acidic functional
group in (Sp)-1 is chiral.
Figure 3. CH/π interactions to form a 21-column (side view) in
the less-soluble (Sp)-1‚(R)-2d. The red dashed lines indicate CH/π
interactions.
We could not determine the crystal structures of the
corresponding more-soluble diastereomeric salts, because
they were always oils even at low temperatures. However,
the IR spectra in a region of 3100-2700 cm-1 assignable to
the vibrations of the hydrogen bonds were similar to each
other for the crystalline less-soluble salt and the oily more-
soluble salt of 2d with (Sp)-1. Although the similarity of
the IR spectra is not direct evidence, it would suggest the
formation of a similar spherical cluster in the more-soluble
diastereomeric salt.
On the basis of the consideration that quantitative informa-
tion for the stability of the diastereomeric salts would be
obtained owing to their definite hydrogen-bonding networks,
we next carried out theoretical calculations for the less- and
more-soluble salt clusters of 2d with (Sp)-1. Geometries of
the cluster units were optimized with B3LYP/3-21G*.11 The
optimized structures are shown in Figure 4. The hydrogen-
bonding networks located at the centers of the spherical
clusters are very similar to each other, and no significant
difference in molecular repulsion can be observed between
the optimized structures. However, the orientations of the
molecules of 2d to the molecule of (Sp)-1 in the spherical
clusters are remarkably different from each other. In the less-
soluble salt cluster, the aromatic ring of (R)-2d locates closely
and vertically to the aromatic ring of (Sp)-1 so that three
(9) (a) Jaques, J.; Collet, A.; Wilen, S. H. In Enantiomers, Racemates
and Resolution; Krieger Publishing Company: Malabor, FL, 1994. (b)
Akazome, M.; Takahashi, T.; Ogura, K. J. Org. Chem., 1999, 64, 2293-
2300. (c) Akazome, M.; Senda, K.; Ogura, K. J. Org. Chem. 2002, 67,
8885-8889. (d) Kinbara, K.; Saigo, K. In Topics in Stereochemistry;
Denmark, S. C., Ed.; Wiley & Sons: New York, 2003; Vol. 3, Chapter 4.
(e) Sada, K.; Inoue, K.; Tanaka, T.; Tanaka, A.; Nagahama, S.; Matsumoto,
A.; Miyata, M. J. Am. Chem. Soc. 2004, 126, 1764-1771.
(10) Very recently, the formation of a spherical cluster consisting of four
carboxylic acid molecules and four amine molecules was reported. However,
the carboxylic acid and amine are achiral; no chiral recognition phenomenon
was observed. Sada, K.; Watanabe, T.; Miyamoto, J.; Fukuda, T.; Tohnami,
N.; Miyata, M.; Kitayama, T.; Maehara, K.; Ute, K. Chem. Lett. 2004, 160-
161.
(11) Geometry optimizations were performed with B3LYP/3-21G* using
the Gaussian 98 package. Frisch, M. J. et al. Gaussian 98, Revision A.11;
Gaussian, Inc.: Pittsburgh, PA, 1998 [Full reference is given in Supporting
Information]. For the initial coordinates of the more-soluble salt, the
enantiomeric molecules of the amine component in the less-soluble salt
crystal were replaced by the antipodes.
Org. Lett., Vol. 6, No. 23, 2004
4229

sulfonic acids, and phosphoric acids. The energy difference
between the two spherical clusters was estimated to be 16.2
kcal/mol. Although this energy difference seems to be
considerably overestimated, the preferential stabilization of
one of the two diastereomeric clusters, giving the less-soluble
salt as crystals at room temperature and the more-soluble
salt as oil even at low temperature, would be reasonably
explained on the basis of the energy difference. The
calculations also suggest that the chiral recognition would
occur during the construction of the spherical clusters in a
solution prior to crystallization.
In conclusion, we demonstrated an excellent chiral rec-
ognition ability of (Sp)-O-ethyl phenylphosphonothioic acid
((Sp)-1) for various racemic 1-phenylethylamine derivatives.
The X-ray crystallographic analyses revealed that a very
unique spherical cluster, in which there existed a definite
hydrogen-bonding network, was formed to realize the
excellent chiral recognition ability of (Sp)-1. Moreover,
theoretical calculations suggested that the prediction of the
chiral recognition ability of (Sp)-1 for a given racemic amine
would be possible, since the hydrogen-bonding network in
the spherical cluster is definite.
Figure 4. Molecular clusters of (a) (Sp)-1‚(R)-2d and (b) (Sp)-1‚
(S)-2d optimized with B3LYP/3-21G*. The values are the distances
between the C atom to the π-plane in angstroms.
Acknowledgment. We thank Prof. Takuzo Aida, ERATO
Nanospace Project, JST, for the permission to use a single
crystal X-ray diffractometer.
Supporting Information Available: Experimental pro-
cedure and characterization for (Sp)-1; general procedure for
the enantioseparation by (Sp)-1; FT-IR spectra of the less-
soluble salt (Sp)-1‚(R)-2d and the more-soluble salt (Sp)-1‚
(S)-2d; preliminary crystal data for (Sp)-1‚(R)-2a, (Sp)-1‚
(R)-2g, (Sp)-1‚(R)-2h; and CIF data of (Sp)-1‚(R)-2d, (Sp)-
1‚(R)-2g, and (Sp)-1‚(R)-2h. This material is available free
of charge via the Internet at http://pubs.acs.org.
kinds of CH/π interactions exist between the molecules of
(Sp)-1 and (R)-2d (Figure 4a), whereas there is only one
CH/π interaction in the more-soluble salt cluster. The
formation of the hydrophobic shell and the difference of the
molecular orientation would arise from the chiral phosphorus
atom in (Sp)-1; the P-chiral phosphonothioic acid would
make its substituents more dendritic and give a more
rigorously controlled chiral environment than conventional
acidic resolving agents such as enantiopure carboxylic acids,
OL0483145
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Org. Lett., Vol. 6, No. 23, 2004