Guest dependent inversion of enantiomeric recognition in dehydrocholic acid host-guest enclathration

Article abstract of DOI:10.1016/j.tetasy.2007.05.011

A guest dependent inversion of enantiomeric recognition operated by the host dehydrocholic acid on a second guest is observed during host-guest dehydrocholic acid-sulfoxide assembly formation.

Full text of DOI:10.1016/j.tetasy.2007.05.011

Tetrahedron: Asymmetry 18 (2007) 1194–1196
Guest dependent inversion of enantiomeric recognition in
dehydrocholic acid host–guest enclathration
Olga Bortolini,a Giancarlo Fantin,b,* Marco Fogagnolob and Daniela Perronec
a
`
Dipartimento di Chimica, Universita dlla Calabria, Via Bucci 12C, 87036 Rende, CS, Italy
b
`
Dipartimento di Chimica, Universita di Ferrara, Via Borsari 46, 44100 Ferrara, Italy
`
Dipartimento di Biologia ed Evoluzione, Universita di Ferrara, Via Borsari 46, 44100 Ferrara, Italy
c
Received 2 May 2007; accepted 15 May 2007
Abstract—A guest dependent inversion of enantiomeric recognition operated by the host dehydrocholic acid on a second guest is
observed during host–guest dehydrocholic acid–sulfoxide assembly formation.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
eral aryl methyl sulfoxides.3 In particular, methyl tolyl sulf-
oxide (Tol) 2 is efficiently resolved in its (R)-form with an
ee value of 99%, whereas methyl phenyl sulfoxide (Phe) 3
is obtained as an (S)-enantiomer with an ee value of
36%. Therefore, dehydrocholic acid represents the host of
choice for this class of compounds.4
One of the most important features of supramolecular
chemistry is molecular recognition, by which molecules
selectively bind to form well-defined structures held
together by intermolecular forces largely composed of non-
covalent interactions, such as hydrogen bonding.1 The field
directly derived from this area is host–guest chemistry,
where a host compound spatially incorporates a guest
molecule within its confines. An important application of
host–guest chemistry is the separation of similar com-
pounds by enclathration.2 This involves the choice of a
suitable host compound, which selectively combines with
a particular guest forming crystalline inclusion compounds.
In 2000, we reported the novel observation that dehydro-
cholic acid (3,7,12-triketo-5b-cholan-24-oic acid) 1, a bile
acid derivative lacking steroidal hydroxyl groups, can serve
as a host molecule for host–guest optical resolution of sev-
O
O
CH3
S
S
CH3
CH3
2
3
2. Results and discussion
Competition experiments among similar guests represent
the most direct test for establishing the selectivity with
respect to a given host and several examples have
appeared in the recent literature.5 For a two component
system, three types of selectivities are usually observed: zero,
modest or high, the three cases being well characterized by
a specific selectivity curve.2 The procedure for competition
experiments consists of the preparation of mixtures of the
two guests, in an appropriate solvent, such that the mole
fraction of a given guest varies from 0 to 1. The host is
added to each mixture and the resulting crystalline inclu-
sion compound is analyzed by a suitable technique. The
results of the competition experiment between methyl tolyl
O
COOH
O
O
1
*
Corresponding author. Fax: +39 0532 240709; e-mail: fnn@unife.it
0957-4166/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2007.05.011

O. Bortolini et al. / Tetrahedron: Asymmetry 18 (2007) 1194–1196
1195
Table 1. Enantiomeric excesses and absolute configuration of included
methyl phenyl sulfoxide as a function of the mole fraction of racemic Tol
sulfoxide and methyl phenyl sulfoxide versus dehydrocho-
lic acid are illustrated in Figure 1, where XTol is the mole
fraction of the guest Tol in the liquid solution and ZTol is
the mole fraction of the same guest, included in the host.
Entry
XTol
ee % (absolute configuration)
of included Phea
1
2
3
4
5
6
7
0
36 (S)
0
According to Ward,6 the selectivity coefficient KTol/Phe can
be defined as
0.09
0.28
0.48
0.68
0.89
1
45 (R)
58 (R)
56 (R)
52 (R)
—
KTol=Phe ¼ðKPhe=TolÞꢀ1 ¼ ZTol=ZPhe ꢁ XPhe=XTol
ðXTol þ XPhe ¼ 1Þ
and easily calculated from the data of Figure 1. The results
of competition experiments between Tol and Phe, illus-
trated in Figure 1, showed that methyl tolyl sulfoxide is
preferentially enclathrated over methyl phenyl sulfoxide
by dehydrocholic acid for the hole concentration range
and that the experimental points lie close to a selectivity
coefficient of 5.1. It is noteworthy that KTol/Phe reaches
the highest value of 6.6 when the two guests are present
in nearly equimolar amounts (XTol = 0.48).
a The absolute configuration of Phe recovered from the crystals was
determined by comparison with pure samples, see Ref. 7.
dehydrocholic acid as (S)-enantiomer in 72% enantiomeric
excess (entry 1 of Table 2), in almost two times the ee value
of that found in the conditions reported in Table 1, entry 1.
Increasing the amounts of (R)-methyl tolyl sulfoxide, with
respect to a constantly maintained 1:1 Tol/Phe ratio, how-
ever, overturned the enantiomeric recognition operated by
the bile acid towards a progressive enclathration of Phe
(R)-enantiomer, up to an ee value of 83%.
With these results in hand we turned our attention to a pos-
sible guest exchange between crystals of 1Æ(R)-Tol8 [or
1Æ(S)-Tol9] and Phe dissolved in an appropriate solvent,
which would reveal how strongly the host framework inter-
acts with the guest molecule. Few reports were found in the
literature dealing with guest exchange in inclusion crystals
in solid-solution biphase.10 The exchange experiments were
performed on standing the inclusion compound, that is,
1Æ(R)-Tol [or 1Æ(S)-Tol], with racemic phenyl methyl sulfox-
ide guest, dissolved in ether/ethyl acetate 1:1 for 48 h. After
this time the solid was filtered, washed, treated with aque-
ous NaHCO3, extracted with ethyl acetate and analyzed by
GC. The 1Æ(R)-Tol complex exchanges the 15% of the in-
cluded (R)-Tol with the guest Phe, which in turn is included
within the dehydrocholic acid as (R)-Phe, with an enantio-
meric excess of 65%. On the other hand, the 1Æ(S)-Tol
Figure 1. Selectivity of Tol with respect to Phe; the calculated selectivity
coefficient is of 5.1.
Table 1 reports the enantiomeric excesses measured for the
included methyl phenyl sulfoxide as a function of the molar
fraction of Tol in liquid solution, in the competition exper-
iments described above. In the absence of Tol, methyl
phenyl sulfoxide is preferentially included within dehydro-
cholic acid as the (S)-enantiomer in 36% enantiomeric
excess, confirming our previous reports.3 The presence of
racemic methyl tolyl sulfoxide in increasing amounts with
respect to Phe, however, results in an inversion of the enan-
tiomeric recognition, revealed as inclusion of the methyl
phenyl sulfoxide (R)-enantiomer. It should be noted that
also in this case the maximum effect in terms of enantio-
meric excess is observed when the two guests are present
in equimolar amounts (XTol = 0.48, entry 4 of Table 1).
Table 2. Enantiomeric excesses and absolute configuration of included
methyl phenyl sulfoxide as a function of the mole fraction of optically
active (R)-Tol and (S)-Tol
Entrya
X(R)-Tol
X(S)-Tol
ee % (absolute configuration)
of included Phe
1
2
3
4
5
6
7
8
9
0
1
72 (S)
72 (S)
61 (S)
19 (S)
30 (R)
72 (R)
80 (R)
81 (R)
82 (R)
83 (R)
83 (R)
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
Since equimolar amounts of the two guests in the liquid
solution showed the highest influence both on selectivity
and on the inversion of enantiomeric recognition, a Tol/
Phe ratio of 1:1 has been used to study the influence of
optically active Tol on included Phe. As shown in Table
2 the enantioselective enclathration of Phe is strongly influ-
enced by the co-presence of Tol and especially by its enan-
tiomeric enrichment in one of the two components,
expressed as X(R)-Tol or X(S)-Tol. When (S)-Tol is exclusively
present in the liquid solution, in fact, Phe is included within
10
11
a Ratio Tol/Phe 1:1 (Tol = (S)-Tol + (R)-Tol in different mole fractions);
the absolute configuration of Phe recovered from the crystals was
determined by comparison with pure samples, see Ref. 7; the amount of
Tol and Phe included in 1 for each experiment is reported in Section 4.

1196
O. Bortolini et al. / Tetrahedron: Asymmetry 18 (2007) 1194–1196
complex exchanges the included (S)-Tol with the guest Phe
(exchange yield 7%) that is included in 1 as (S)-Phe with an
enantiomeric excess of 70%.
82:18, #3 88:12, # 4 88:12, #5 86:14, #6 87:13, #7 90:10,
#8 90:10, #9 90:10, #10 91:9, #11 91:9.
References
3. Conclusion
1. (a) Comprehensive Supramolecular Chemistry; Lehn, J.-M.,
Atwood, J. L., Davies, J. E. D., MacNicol, D. D., Vo¨gtle, F.,
Eds.; Pergamon: New York, 1996; Vol. 1–3, (b) Jeffrey, G. A.
In An Introduction to Hydrogen Bonding; Oxford University
Press: Oxford, 1997.
2. (a) Toda, F. In Enantiomer Separation. Fundamentals and
Practical Methods; Toda, F., Ed.; Kluwer, 2004; pp 1–56; (b)
Nassimbeni, L. R. In Separation and Reactions in Organic
Supramolecular Chemistry: Perspectives in Supramolecular
Chemistry; Toda, F., Bishop, R., Eds.; Wiley, 2004; Vol. 8, pp
123–135.
Both results are in agreement with the data reported in
Table 2 and further support the occurring guest exchange
in inclusion compounds, and even more importantly, the
guest dependent inversion of enantiomeric recognition
operated by the host. We were able to demonstrate the
possibility of obtaining the control of the enantiomeric
inclusion on (R)- or (S)-methyl phenyl sulfoxide in de-
hydrocholic acid assemblies via supramolecular chiral
recognition induced by a second guest, that is (R)- or (S)-
Tol. To the best of our knowledge, this is the first example
of stereochemical information transfer controlled by a
guest on a host, with respect to another guest.
3. Bortolini, O.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini,
P. Chem. Commun. 2000, 365–366.
4. Bortolini, O.; Fantin, G.; Fogagnolo, M. Chirality 2005, 17,
121–130.
5. Nassimbeni, L. R. Acc. Chem. Res. 2003, 36, 631–637.
6. Pivotar, A. M.; Holman, K. T.; Ward, M. D. Chem. Mater.
2001, 13, 3018–3031.
4. Experimental
7. (a) Komatsu, N.; Hashizume, M.; Sugita, T.; Uemura, S. J.
Org. Chem. 1993, 58, 4529–4533; (b) Brunel, J. M.; Diter, P.;
Duetsch, M.; Kagan, H. B. J. Org. Chem. 1995, 60, 8086–
8088; (c) Donnoli, M. I.; Supelchi, S.; Rosini, C. J. Org.
Chem. 1998, 63, 9392–9395; (d) Di Furia, F.; Licini, G.;
Modena, G.; Motterle, R.; Nugent, W. A. J. Org. Chem.
1996, 61, 5175–5177.
A typical procedure for competition experiments between
Tol and Phe consists of the preparation of several mixtures
of the two guests in different Tol/Phe molar fraction: 0:10,
1:9, 3:7, 5:5, 7:3, 9:1, 10:0, for a total amount of Tol/Fen of
2.7 mmols dissolved in ether/ethyl acetate 1:1 (2.8 mL).
The solid host dehydrocholic acid 1 is added (0.124 mmol).
The biphasic system is allowed to stand for 48 h. The solid
inclusion compound is filtered, treated with aqueous NaH-
CO3, extracted and the guest content, including enantio-
meric excesses, analyzed by GC on a chiral column
Megadex DETTBS. Absolute configurations of the sulfox-
ides recovered from the crystals were determined by com-
parison with pure samples: Phe, prepared according to
the literature procedures;7 Tol, commercially available. A
typical procedure for competition experiments between
optically active Tol and Phe consists of the preparation
of mixtures of the two guests in equimolar concentration,
but progressively increasing the percentages of the (R)-
Tol over the (S)-enantiomer, dissolved in ether/ethyl ace-
tate 7:3. Host 1 is added maintaining a ratio Tol/Phe/1
of 3:3:1. The amounts of Tol and Phe included in 1 for each
experiment of Table 2 are Tol/Phe entry #1 80:20, #2
8. Bertolasi, V.; Bortolini, O.; Fantin, G.; Fogagnolo, M.;
Medici, A. Chem. Lett. 2002, 400–401.
9. Fantin, G.; Fogagnolo, M.; Bortolini, O.; Masciocchi, N.;
Galli, S.; Sironi, A. New J. Chem. 2004, 28, 1295–1300.
10. (a) Shibakami, M.; Tamura, M.; Sekiya, A. J. Am. Chem.
Soc. 1995, 117, 4499–4505; (b) Endo, K.; Ezuhara, T.;
Koyanagi, M.; Masuda, H.; Aoyama, Y. J. Am. Chem. Soc.
1997, 119, 499–505; (c) Endo, K.; Sawaki, T.; Koyanagi, M.;
Kobayashi, K.; Masuda, H.; Aoyama, Y. J. Am. Chem. Soc.
1995, 117, 8341–8352; (d) Wang, X.; Simard, M.; Wuest, J. D.
J. Am. Chem. Soc. 1994, 116, 12119–12120; (e) Yaghi, O. M.;
Davis, C. E.; Li, G.; Li, H. J. Am. Chem. Soc. 1997, 119,
2861–2868; (f) Gardner, G. B.; Kiang, Y.-H.; Lee, S.;
Asgaonkar, A.; Venkataraman, D. J. Am. Chem. Soc. 1996,
118, 6946–6953; (g) Biradha, K.; Dennis, D.; MacKinnon, V.
A.; Sharma, C. V. K.; Zaworotko, M. J. J. Am. Chem. Soc.
1998, 120, 11894–11903; (h) Akazome, M.; Hirabayashi, A.;
Ogura, K. Tetrahedron 2004, 60, 12085–12093.