Spontaneous resolution of aromatic sulfonamides: Effective screening method and discrimination of absolute structure

Article abstract of DOI:10.1021/ol061731s

(Chemical Equation Presented) An effective screening method combining parallel synthesis and solid-state CD measurements was established to identify achiral aromatic sulfonamides that show spontaneous resolution with rapidity. We found that 4 of the 12 achiral sulfonamides crystallized as chiral crystals through this method. The chirality of each sulfonamide was discriminated by solid-state CD spectra and Flack parameter in an X-ray analysis. Correspondence between the observed Cotton effect and the absolute configuration could be confirmed by time-dependent DFT calculations.

Full text of DOI:10.1021/ol061731s

ORGANIC
LETTERS
2006
Vol. 8, No. 22
5017-5020
Spontaneous Resolution of Aromatic
Sulfonamides: Effective Screening
Method and Discrimination of Absolute
Structure
|
,
Takako Kato,† Iwao Okamoto,‡ Aya Tanatani,§ Terutaka Hatano,
|
Masanobu Uchiyama, Hiroyuki Kagechika, Hyuma Masu,† Kosuke Katagiri,†
Masahide Tominaga,† Kentaro Yamaguchi,† and Isao Azumaya*,†
Faculty of Pharmaceutical Sciences at Kagawa Campus, Tokushima Bunri UniVersity,
1314-1 Shido, Sanuki, Kagawa 769-2193, Japan, Showa Pharmaceutical UniVersity,
Higashi-tamagawagakuen, Machida, Tokyo 194-8543, Japan, Faculty of Science,
Ochanomizu UniVersity, Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan, AdVanced
Elements Chemistry Laboratory, RIKEN (Institute of Physical and Chemical Research),
2-1 Hirosawa, Wako, Saitama 351-0198, Japan, and School of Biomedical Science,
Tokyo Medical and Dental UniVersity, Kanda-Surugadai, Chiyoda-ku,
Tokyo 101-0062, Japan
azumayai@kph.bunri-u.ac.jp
Received July 14, 2006
ABSTRACT
An effective screening method combining parallel synthesis and solid-state CD measurements was established to identify achiral aromatic
sulfonamides that show spontaneous resolution with rapidity. We found that 4 of the 12 achiral sulfonamides crystallized as chiral crystals
through this method. The chirality of each sulfonamide was discriminated by solid-state CD spectra and Flack parameter in an X-ray analysis.
Correspondence between the observed Cotton effect and the absolute configuration could be confirmed by time-dependent DFT calculations.
The spontaneous resolution of an achiral compound (total
asymmetric transformation) has been of great interest in
connection with the origin of life.1 This phenomenon also
holds potential in that the spontaneously resolved chiral
crystals could find application as chiral sources in asymmetric
synthesis to produce compounds with fixed chirality. In this
point of view, several approaches have been successful. For
example, a photoreaction in the chiral crystalline state of
achiral compounds produced high enantioselectivities.2 Con-
formational chirality, which is retained when chiral crystals
are dissolved at low temperature, has been utilized in
(1) (a) Cohen, M. D.; Schmidt, G. M. J. J. Chem. Soc. 1964, 1996-
2000. (b) Schmidt, G. M. J. Pure Appl. Chem. 1971, 27, 647-678. (c)
Elias, W. E. J. Chem. Educ. 1972, 49, 448-454. (d) Pincock, R. E.; Wilson,
K. R. J. Chem. Educ. 1973, 50, 455-457. (e) Green, B. S.; Lahav, M.;
Rabinovich, D. Acc. Chem. Res. 1979, 12, 191-197. (f) Addadi, L.; Lahav,
M. In Origin of Optical Activity in Nature; Walker, D. C., Ed.; Elsevier:
Amsterdam, The Netherlands, 1979; Chapter 14. (g) Mason, S. F. Nature
(London) 1984, 311, 19-23. (h) Kaupp, G.; Haak, M. Angew. Chem., Int.
Ed. Engl. 1993, 32, 694-695.
(2) (a) Toda, F.; Yagi, M.; Soda, S. J. Chem. Soc., Chem. Commun.
1987, 1413-1414. (b) Sakamoto, M. Chem. Eur. J. 1997, 3, 684-689. (c)
Sakamoto, M.; Iwamoto, T.; Nono, N.; Ando, M.; Arai, W.; Mino, T.; Fujita,
T. J. Org. Chem. 2003, 68, 942-946. (d) Koshima, H.; Kawanishi, H.;
Nagano, M.; Yu, H.; Shiro, M.; Hosoya, T.; Uekusa, H.; Ohashi, Y. J.
Org. Chem. 2005, 70, 4490-4497.
† Tokushima Bunri University.
‡ Showa Pharmaceutical University.
§ Ochanomizu University.
| RIKEN.
Tokyo Medical and Dental University.
10.1021/ol061731s CCC: $33.50
© 2006 American Chemical Society
Published on Web 10/03/2006

diastereoselective syntheses.3 Another approach is to utilize
the spontaneously resolved chiral crystals as catalytic ligands
to produce chiral compounds with fixed chirality.4 Such an
approach, however, is limited mainly because the spontane-
ous resolution of an achiral compound does not occur so
frequently. During the course of our study on the stereo-
chemistry of aromatic amides or sulfonamides,5,6 we found
that several groups of compounds with a common skeleton
showed spontaneous resolution more frequently than other
achiral compounds.6 In this context, the development of a
rapid screening method for spontaneous resolution would
provide new insights into the field of asymmetric or
diastereoselective synthesis. In this paper, we report an
effective screening method for spontaneous resolution of
aromatic sulfonamides, which relies on parallel syntheses
and solid-state CD measurements. Furthermore, we also
determined the absolute structures of several sulfonamides
by X-ray crystallographic analysis, and showed that the
corresponding CD spectra calculated from the absolute
structures with the time-dependent DFT method7 were
consistent with the observed solid-state CD spectra.8
A schematic representation of the screening method for
spontaneous resolution of aromatic sulfonamides is shown
in Figure 1. Substituted anilines (0.1 mmol), substituted
sulfonyl chlorides (0.1 mmol), and polymer-supported py-
ridine (5 equiv) in 1.0 mL of solvent (dichloromethane or
chloroform) were mixed together and stirred until the reaction
was complete. The polymer-supported pyridine was filtered
off and the filtrate was evaporated to give single crystals, or
slowly evaporated with stirring to give powder-like micro-
crystals of the corresponding sulfonamides. The sulfonamide
crystals were ground together with KBr and pressed under
reduced pressure to give a transparent discotic tablet (10-
mm diameter). Then, solid-state CD spectra of the discotic
tablets were measured.
Figure 1. Procedure for rapid screening of sulfonamides showing
spontaneous resolution.
Practically, the weight of crystal needed for solid-state CD
measurement is 50-200 µg per KBr tablet (100 mg of KBr).
When the weight of a single crystal is less than 50 µg, the
overall mass of microcrystals obtained by slow evaporation
of the solvent with stirring can be used. As a matter of course,
all molecules in a spontaneously resolved single crystal have
the same chirality. In addition to this, the entire number of
microcrystals formed in a flask obtained by slow evaporation
of the solvent with stirring tends to have high enantiomeric
purity, because the chirality of the first generated crystal seed
diffuses throughout the whole flask during stirred crystal-
lization (see ref 9).
(3) (a) Sakamoto, M.; Iwamoto, T.; Nono, N.; Ando, M.; Arai, W.; Mino,
T.; Fujita, T. J. Org. Chem. 2003, 68, 942-946. (b) Sakamoto, M.; Kobaru,
S.; Mino, T.; Fujita, T. Chem. Commun. 2004, 1002-1003.
The developed procedure was performed for the following
16 combinations including aniline, N-methylaniline, 4-meth-
oxyaniline, and 4-nitroaniline as amines, and benzenesulfonyl
chloride, 4-methoxybenzenesulfonyl chloride, 4-nitrobenze-
nesulfonyl chloride, and mesitylenesulfonyl chloride as acid
chlorides. 4-Nitroaniline did not react with sulfonyl chlorides
because of the low nucleophilicity at the nitrogen atom, even
when the reaction mixture was heated at reflux in chloroform.
Four of the twelve sulfonamides (1, 2, 3, and 4) revealed
Cotton effects in the corresponding CD spectra (Table 1).
Surprisingly, compound 4, which showed Cotton effects, was
previously reported to crystallize as achiral crystals by
another group.10b
(4) Tissot, O.; Gouygou, M.; Dallemer, F.; Daran, J.-C.; Balavoine, G.
G. A. Angew. Chem., Int. Ed. 2001, 40, 1076-1078.
(5) (a) Itai, A.; Toriumi, Y.; Tomioka, N.; Kagechika, H.; Azumaya, I.;
Shudo, K. Tetrahedron Lett. 1989, 30, 6177-6180. (b) Azumaya, I.;
Kagechika, H.; Fujiwara, Y.; Itoh, M.; Yamaguchi, K.; Shudo, K. J. Am.
Chem. Soc. 1991, 113, 2833-2838. (c) Yamaguchi, K.; Matsumura, G.;
Kagechika, H.; Azumaya, I.; Ito, Y.; Itai, A.; Shudo, K. J. Am. Chem. Soc.
1991, 113, 5474-5475. (d) Itai, A.; Toriumi, Y.; Saito, S.; Kagechika, H.;
Shudo, K. J. Am. Chem. Soc. 1992, 114, 10649-10650. (e) Azumaya, I.;
Kagechika, H.; Yamaguchi, K.; Shudo, K. Tetrahedron 1995, 51, 5277-
5290. (f) Tanatani, A.; Yamaguchi, K.; Azumaya, I.; Fukutomi, R.; Shudo,
K.; Kagechika, H. J. Am. Chem. Soc. 1998, 120, 6433-6442.
(6) (a) Azumaya, I.; Yamaguchi, K.; Okamoto, I.; Kagechika, H.; Shudo,
K. J. Am. Chem. Soc. 1995, 117, 9083-9084. (b) Azumaya, I.; Okamoto,
I.; Nakayama, S.; Tanatani, A.; Yamaguchi, K.; Shudo, K.; Kagechika, H.
Tetrahedron 1999, 55, 11237-11246. (c) Azumaya, I.; Okamoto, I.;
Takayanagi, H. Anal. Sci. 2003, 19, 3-4. (d) Azumaya, I.; Kato, T.;
Okamoto, I.; Yamasaki, R.; Tanatani, A.; Yamaguchi, K.; Kagechika, H.;
Takayanagi, H. Org. Lett. 2003, 5, 3939-3942.
(7) (a) Furche, F.; Ahlrichs, R.; Wachsmann, C.; Weber, E.; Sobanski,
A.; Vo¨gtle, F.; Grimme, S. J. Am. Chem. Soc. 2000, 122, 1717-1724. (b)
Stephens, P. J.; Devlin, F. J.; Cheeseman, J. R.; Frisch, M. J.; Rosini, C.
Org. Lett. 2002, 4, 4595-4598. (c) Wang, Y.; Raabe, G.; Repges, C.;
Fleischhauer, J. Int. J. Quantum Chem. 2003, 93, 265-270. (d) Jorge, F.
E.; Autschbach, J.; Ziegler, T. J. Am. Chem. Soc. 2004, 127, 975-985. (e)
Voloshina, E.; Fleischhauer, J.; Kraft, P. HelV. Chim. Acta 2005, 88, 194-
209. (f) Sˇebek, J.; Kej´ık, Z.; Bourˇ, P. J. Phys. Chem. A 2006, 110, 4702-
4711.
Next, those sulfonamides which showed spontaneous
resolution were synthesized in large quantities by using a
general method. Compounds 1, 2, and 3 were crystallized
from chloroform to give prismatic single crystals. Each
(9) (a) Kondepudi, D. K. J. Am. Chem. Soc. 1999, 121, 1448-1449. (b)
Sakamoto, M.; Utsumi, N.; Ando, M.; Saeki, M.; Mino, T.; Fujita, T.; Katoh,
A.; Nishio, T.; Kashima, C. Angew. Chem., Int. Ed. 2003, 42, 4360-4363.
(10) (a) Osawa, Y. Nippon Kagaku Zasshi 1963, 84, 134-137. (b)
Pokrywiecki, S.; Weeks, C. M.; Duax, W. L. Acta Crystallogr., Sect. C:
Cryst. Struct. Commun. 1973, 2, 63-66.
(8) Kuroda, R.; Honma, T. Chirality 2000, 12, 269-277.
5018
Org. Lett., Vol. 8, No. 22, 2006

Conformations of the enantiomers of sulfonamides 1, 2, and
3 in the crystals are shown in Figure 3. Both secondary and
Table 1. Results of the Rapid Screening for Spontaneous
Resolution (Optical Activity Seen in the CD Spectra) of
Aromatic Sulfonamides
Figure 3. Conformations of each enantiomer (left: +synclinal;
right: -synclinal) of sulfonamides (a) 1, (b) 2, and (c) 3 in the
crystals.
crystal was then divided, and a single piece was ground with
KBr to give discotic samples for solid-state CD analysis.
Tablet preparation was repeated for each crystal until suitable
mirror-imaged CD spectra of both enantiomeric crystals were
obtained for each compound. Figure 2a-c shows the CD
spectra of spontaneously resolved chiral crystals of sulfona-
mides 1, 2, and 3. The crystals of compound 4 did not show
any Cotton effect contrary to the result of our rapid screening
method. Therefore, several recrystallizations under slow
evaporation with stirring were performed in order to obtain
both (+) and (-) CD spectra (Figure 2d).
tertiary sulfonamides exist in the synclinal conformation, as
well as the related aromatic sulfonamide derivatives so far
reported6d,12 (Table 2). The +synclinal and -synclinal
Table 2. Torsion Angle (deg) of Ar-N-S-Ar in the Crystal
of Compounds 1-3
1
2
3
+synclinal
-synclinal
58.15
-58.44
72.52
-72.44
83.09
-83.25
conformations are enantiomeric to each other. In the case of
the spontaneous resolution of secondary sulfonamides (1 and
2), infinite chained structures were formed through hydrogen
bonds between the conformers, with a single chirality along
either the b-axis (compound 1) or a-axis (compound 2)
observed in the crystal.
No remarkable intermolecular interaction was observed
in the chiral crystal of the tertiary sulfonamide 3, and the
single enantiomeric conformer was just packed into the unit
cell. The crystal of compound 4, obtained through a typical
recrystallization method, belongs to the achiral space group
P21/c and shows a melting point of 93 °C, properties which
are intrinsically the same as those previously reported by
other groups.10 On the other hand, the crystal of compound
4 that showed Cotton effects in the solid-state CD spectra
was observed to melt at 99 °C, which is apparently different
from that of the achiral crystal. Moreover, crystals obtained
through the melt-solidification of achiral crystals showed
Cotton effects and revealed a melting point of 99 °C. This
means that compound 4 exhibits crystal polymorphism,
showing both chiral and achiral forms.5f,13
Figure 2. Solid-state CD spectra of enantiomeric crystals (in KBr)
of sulfonamides (a) 1, (b) 2, (c) 3, and (d) 4.
X-ray crystallographic analyses of a pair of enantiomeric
crystals of compounds 1-3 were performed and each
enantiomer was discriminated according to the Flack pa-
rameter method.11 Thus, the sign of the Cotton effect could
be related to the absolute structure for compounds 1-3 (red
line: +synclinal; blue line: -synclinal in Figure 2a-c).
(12) (a) Adsmond, D. A.; Grant, D. J. W. J. Pharm. Sci. 2001, 90, 2058-
2077. (b) Kato, T.; Masu, H.; Takayanagi, H.; Kaji, E.; Katagiri, K.;
Tominaga, M.; Azumaya, I. Tetrahedron 2006, 62, 8458-8462.
(13) (a) Gonnade, R. G.; Bhadbhade, M. M.; Shashidhar, M. S. Chem.
Commun. 2004, 2530-2531. (b) Sakamoto, M.; Kobaru, S.; Kasashima,
Y.; Mino, T.; Fujita, T. Tetrahedron Lett. 2005, 46, 4439-4442.
(11) Flack, H. D. Acta Crystallogr. 1983, A39, 876-881.
Org. Lett., Vol. 8, No. 22, 2006
5019

effect in the observed solid-state CD spectra, taking into
account the general tendency of UV absorption red-shifts in
the solid-state compared to that in the solvent.14 For example,
in both the +synclinal and -synclinal crystals of compound
1, the Cotton effect sign occurred around 220 nm in the
predicted spectra (Figure 4a), corresponding to that in the
observed spectra (Figure 2a).
The TD-DFT calculations of compound 4, the absolute
structure of which was not determined by X-ray analysis,
were performed on the basis of the structure of the B3LYP-
optimized geometry constructed from the coordinates of the
analogue. The Cotton effect sign occurred around 260 nm
in the predicted spectra (Figure 4d), corresponding to that
in the observed spectra (Figure 2d) in the +synclinal and
-synclinal conformations. Thus, the red and blue CD spectra
in Figure 2d are expected to correspond to the +synclinal
and -synclinal conformations, respectively.
In conclusion, we established a rapid screening method
for the spontaneous resolution of aromatic sulfonamides, and
reported that four achiral sulfonamides gave chiral crystals,
as confirmed by solid-state CD measurements and X-ray
crystallographic analysis. In addition, we determined the
absolute structure of these sulfonamides based on the Flack
parameter method and a comparison of the observed solid-
state CD spectra with the corresponding predicted spectra
calculated with the TD-DFT method. We believe that our
proposed method will help design asymmetric or diastereo-
selective syntheses with use of spontaneously resolved chiral
crystals as a chiral source because it has become easy to
find spontaneously resolved compounds which have a small
or moderate energy barrier in racemization, that is, will be
utilized as a chiral source, by being dissolved in a solvent at
low temperature, in a two-phase reaction where the chiral
crystals remain undissolved, or after UV irradiation to fix
the chirality by covalent bonds.
Figure 4. Predicted CD spectra (left: +synclinal; right: -syn-
clinal) of compounds (a) 1, (b) 2, (c) 3, and (d) 4, calculated by
the time-dependent DFT method (B3LYP/6-31G*), using the
geometries obtained from the corresponding crystal structures (a-
c) or B3LYP-optimized structures (B3LYP/6-31G*) based on
typical synclinal conformations (d). Rotational strengths are given
in cgs (10-40 erg esu cm/G).
Acknowledgment. This work was supported by Grant-
in-Aid for Scientific Research (C) (No. 16590011) from the
Japan Society for the Promotion of Science and a Sasakawa
Scientific Research Grant from The Japan Science Society.
We are thankful for computational resources of the RIKEN
Super Combined Cluster (RSCC).
Supporting Information Available: Synthetic procedure,
spectral data and crystallographic information for sulfona-
mides 1-4. This material is available free of charge via the
Internet at http://pubs.acs.org.
Time-dependent (TD) DFT calculations were performed
to predict the solid-state CD spectra of 1-4. First, CD spectra
of each enantiomer of sulfonamides 1-3 were calculated
by using coordinate data determined by X-ray crystal-
lographic analysis. Figure 4a-c shows the calculated CD
intensities of compounds 1-3. The sign of the Cotton effect
in the predicted spectra correlated with that of the Cotton
OL061731S
(14) Smit, K. J. J. Energ. Mater. 1991, 9, 81-103.
5020
Org. Lett., Vol. 8, No. 22, 2006