Diketobile acids as new hosts in solid-state enantioselective resolutions

Article abstract of DOI:10.1246/cl.2007.930

New diketobile acid derivatives have been evaluated as hosts in the resolution of aryl methyl sulfoxides. The guest molecules are linked to the host ones via hydrogen bonds with the SO group. The 3,6-diketo derivative is also effective for the resolution of γ-lactames. Copyright

Full text of DOI:10.1246/cl.2007.930

930
Chemistry Letters Vol.36, No.7 (2007)
Diketobile Acids as New Hosts in Solid-state Enantioselective Resolutions
Giancarlo Fantin,1 Marco Fogagnolo,Ã1 Daniela Perrone,2 and Olga Bortolini3
1
`
Dipartimento di Chimica, Universita di Ferrara, Via Borsari 46, 44100 Ferrara, Italy
`
2
Dipartimento di Biologia ed Evoluzione, Universita di Ferrara, C.so Ercole I d’Este, 32, 44100 Ferrara, Italy
3
`
Dipartimento di Chimica, Universita della Calabria, Via Bucci 12C, 87036 Rende, Italy
(Received March 27, 2007; CL-070323; E-mail: fgr@unife.it)
Table 1. Optical resolution of methyl tolyl sulfoxide using 2–4
as chiral host
New diketobile acid derivatives have been evaluated as
hosts in the resolution of aryl methyl sulfoxides. The guest
molecules are linked to the host ones via hydrogen bonds with
the SO group. The 3,6-diketo derivative is also effective for
the resolution of ꢀ-lactames.
Host
Host:Guest ratioa
ee%b
abs. config.c
2
3
4
1:1
1:1
1:1
96
93
85
(+)-R
(+)-R
(+)-R
aDetermined by 1H NMR on the formed crystals.
Bile acids, in particular derivatives of cholic acid, are clas-
sical host compounds that form crystalline inclusion clathrate
complexes with various organic guest derivatives. Due to their
asymmetry, these hosts are expected to construct assemblies
with chiral cavities able to accommodate chiral organic guests,
thus allowing optical resolution of racemic compounds.1 In the
enantioselective inclusion complexation of a racemic guest with
a chiral host, in fact, one enantiomer of the former is separated as
an inclusion host–guest complex crystal. From the inclusion
crystal, an optically active guest can be isolated by an appropri-
ate method.1
During our search for new host compounds for racemate
resolution we have evaluated the capability of three diketobile
acid derivatives 2–4,2 comparing their resolution performances
with those of dehydrocholic acid 1, derivative extensively used
in many host–guest resolutions (Scheme 1).3,5
Table 1 reports the pertinent results based on the use of
methyl tolyl sulfoxide as model guest, included within the se-
lected host 2–4 by the co-grinding method.1 According to this
methodology a host–guest mixture is ground in a mortar at room
temperature for 20 min; the solid is washed with Et2O, dissolved
using aqueous NaHCO3 and extracted with Et2O to afford en-
riched (R)-methyl tolyl sulfoxide. Hosts 2 and 3 showed superior
results in terms of enantioresolution, however, host 3 displayed a
more pronounced resistance during work-up and, consequently,
has been selected to investigate the resolution ability toward dif-
ferent classes of organic racemates i.e. aryl methyl sulfoxides
and cyclic amides. Table 2 collects the pertinent results.
In this case, to obtain host–guest inclusion complexes, the
guest was either dissolved in Et2O and added to 3 or vaporized
c
bDetermined by GC using a chiral column. cf. Ref. 3.
at 50 ꢀC in the presence of 3. The inclusion compounds were
then treated as described in previous paragraphs. Compared
with dehydrocholic acid the new host gives rise to comparable
or slightly better results, particularly in the case of cyclic amides,
and may be proposed as suitable host for the resolution of these
compounds.
In previous publications, we have reported and discussed
the crystal structure of the 1:1 inclusion compound between
dehydrocholic acid 1 and (R)-methyl tolyl sulfoxide6 and the
X-ray powder diffraction (XRPD) of 1 with p-XC6H4SOCH3,
X = CH3 and Br, respectively.7,8 In both cases, the packing dia-
grams showed the guest molecules linked to the carboxylic
group of the host by means of a hydrogen bond with the sulf-
˚
oxide moiety, stabilized by COOHÁÁÁOS contacts of 2.63 A for
˚
methyl tolyl sulfoxide and of 2.65 A for p-bromophenyl methyl
sulfoxide.8 Unpublished IR data obtained on isolated compounds
Table 2. Optical resolution of organic racemates using 3 as
host and comparison with the data obtained with dehydrocholic
acid 1
Guest
ee %a
(abs. conf.)b
96 (R)c
Prev. work
99 (R)3
O
67 (R)d
S
H3C
Br
CH3
CH3
85 (R)c
83 (R)d
84 (R)3
64 (R)5
O
S
40 (R)c
23 (R)d
CH3
O
N
H
60 (S)c
36 (S)d
42 (S)5
CH3
O
N
H
aDetermined by GC using a chiral column. bFor absolute config-
urations cf. Ref. 3. cGuest dissolved in Et2O and added to 3. dThe
guest is vaporized at 50 ꢀC in the presence of the solid host.
Scheme 1. Ketobile acids of this study.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.7 (2007)
931
Table 3. Assignment and wavenumbers of the vibrational
bands (KBr) of free bile acids, sulfoxides and inclusion com-
pounds9
Table 4. Assignment and wavenumbers of the vibrational
bands (KBr) cyclic amides and inclusion compounds9
Compound
ν
NH /cm-1
3240
ν
CO /cm-1
1686
Compound
ꢁ
SO/cmÀ1
ꢁ
CO/cmÀ1
1707
CH3
O
1
p-CH3C6H4SOCH3
.
1 p-CH3C6H4SOCH3
1049
1001
N
H
1705, 1716
1704
CH3
3341
1706
3
p-CH3C6H4SOCH3
.
3 p-CH3C6H4SOCH3
.
3
1049
1002
O
N
1692, 1717
1704
H
3
p-BrC6H4SOCH3
3244
3320
1670
1690
1035
1000
.
3 p-BrC6H4SOCH3
1693, 1714,
1732
CH3
O
N
H
.
3 CH3
O
N
O
H
O
S
O
H
O
O
through a hydrogen bond between the nitrogen of the amide
and the carboxylic function i.e. COOHÁÁÁNH, thus explaining
the increase of the NH absorption frequency.
We are currently extending this host–guest readily accessi-
ble and low-cost resolution methodology to enantioselective
hosts having ketobile acid structures.
O
O
S
H O
O
O
Figure 1. Pictorial representation of a possible coordination
between 3 and the guest sulfoxide.
References and Notes
1
and on the 1:1 inclusion complexes showed band shifts clearly
imputable to the COOHÁÁÁOS contacts. Dehydrocholic acid 1 dis-
played, among others, a signal at 1707 cmÀ1, assigned to a CO
stretching that shifted at 1716 cmÀ1 in the inclusion complex.
On the other hand, it should be noted that the sulfoxide group
displays a vibrational mode at 1049 cmÀ1 that moved at
1001 cmÀ1 upon inclusion complexation, Table 3. Similar be-
havior may be found by comparing the IR spectra of the free bile
acid 3 and of the sulfoxides p-XC6H4SOCH3, X = CH3 and Br,
with those of the included complexes.
In agreement with previous interpretations10 the lowering
of the wavenumber of the sulfoxide moiety absorption upon
inclusion is a clear indication that coordination within the
bile acid host occurs, also for these new complexes, through
the sulfoxide group, following a weakening of the bond strength,
as depicted in Figure 1.
O. Bortolini, G. Fantin, M. Fogagnolo, Chirality 2005, 17,
121, and references cited therein.
2
Compounds 1–4 was prepared starting from commercially
available hydroxyl derivative via oxidation with the Jones’
reagent; see: K. Bowden, I. M. Heilbron, E. R. H, Jones,
B. C. L. Weedon, J. Chem. Soc. 1946, 39.
3
4
5
6
7
8
9
O. Bortolini, G. Fantin, M. Fogagnolo, A. Medici, P. Pedrini,
Chem. Commun. 2000, 365.
V. Bertolasi, V. Ferretti, L. Pretto, G. Fantin, M. Fogagnolo,
O. Bortolini, Acta Crystallogr., Sect. B 2005, 61, 346.
O. Bortolini, M. Fogagnolo, G. Fantin, A. Medici, Chem.
Lett. 2003, 32, 206.
V. Bertolasi, O. Bortolini, G. Fantin, M. Fogagnolo, A.
Medici, Chem. Lett. 2002, 400.
G. Fantin, M. Fogagnolo, O. Bortolini, N. Masciocchi, S.
Galli, A. Sironi, New J. Chem. 2003, 27, 1794.
G. Fantin, M. Fogagnolo, O. Bortolini, N. Masciocchi, S.
Galli, A. Sironi, New J. Chem. 2004, 28, 1295.
Supporting Information is available electronically on the
CSJ-Journal Web site, http://www.csj.jp/journals/chem-lett/
index.html.
Table 4 collects the assignment and IR frequences of free
and included molecules for cyclic amides. In this case, a signifi-
cant increase of the NH vibrational mode frequency is observed
upon complexation, associated with a small increase of the car-
bonyl vibrational band.
Taking into account these shifts we may assume that the
coordination of 3 with the included compound is taking place
10 S. Bayari, Z. Kantarci, S. Akyuz, J. Molec. Struct. 1995, 351,
19.
¨
Published on the web (Advance View) June 23, 2007; doi:10.1246/cl.2007.930