Synthesis of new chiral imidazolium salts derived from amino acids: their evaluation in chiral molecular recognition

Article abstract of DOI:10.1016/j.tetasy.2009.03.028

A family of new imidazolium salts derived from natural amino acids has been synthesized and tested for NMR enantiodiscrimination, as chiral shift reagents, of carboxylic acids. These imidazolium receptors contain different structural modifications and the

Full text of DOI:10.1016/j.tetasy.2009.03.028

Tetrahedron: Asymmetry 20 (2009) 999–1003
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Synthesis of new chiral imidazolium salts derived from amino acids: their
evaluation in chiral molecular recognition
*
*
Belén Altava , Dalgi S. Barbosa, M. Isabel Burguete, Jorge Escorihuela, Santiago V. Luis
Departamento de Química Inorgánica y Orgánica, Universitat Jaume I, Avda. Sos Baynat, s/n, 12071 Castellón, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
A family of new imidazolium salts derived from natural amino acids has been synthesized and tested for
NMR enantiodiscrimination, as chiral shift reagents, of carboxylic acids. These imidazolium receptors
contain different structural modifications and the splitting of the signals of the acids, after addition of
the corresponding CSRs, depends on these structural variables. Compound 8b exhibited the strongest chi-
ral solvating properties for racemic Mosher acid and was recognized as a suitable CSR for the determina-
tion of its enantiomeric composition.
Received 9 February 2009
Accepted 16 March 2009
Available online 22 April 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
nic and hydrogen bonding as the driving forces for the interaction
and approached imidazolium salts with the general structure
Due to the importance of chirality in pharmaceutical and bio-
logical chemistry,1 the development of a fast and simple method-
ology for the measurement of enantiomeric purity is an
important target.2 Chiral shift reagents (CSRs) have a good poten-
tial for this purpose, because NMR spectroscopy has the advanta-
ges of good performance and accessibility and because
enantiomeric excesses can be easily determined by adding the re-
agent to a chiral compound in a small amount of a deuterated sol-
vent.2,3 Moreover, the use of non-covalent chiral shift reagents
provides the possibility of carrying out the experiment ‘in situ’,
and the potential for recovering the chiral compound after mea-
surement. Various types of chiral shift reagents have been reported
for carboxylic acids; however, few of them are commercially avail-
able and useful for the application to pharmacologically active pro-
pionic acids. Although many enantioselective carboxylate
receptors have shown their application in chiral resolution,4 few
such receptors can be used as chiral shift reagents to determine
enantiomeric purities of chiral carboxylic acids by 1H NMR accu-
rately. This is often associated with their structural complexity or
to the fact that the 1H chemical shift nonequivalences are too small
to achieve baseline resolution.3e,5
shown in Figure 1 as effective chiral shift reagents. The main struc-
tural variables considered for the synthesis of these imidazolium
salts were the amino acid side chain residue, the aromatic moiety
attached to the nitrogen atom, and the counter anion.
R
OH
N
N
Ph
Ph
Ar
X
5-11
Figure 1. Structural variables in imidazolium salts.
Several chiral imidazolium salts with ionic liquid properties
(CILs) have been described in the literature as good shift reagents
for the potassium salt of the Mosher acid.6 To date, however, there
are only a few examples of chiral imidazolium compounds, pre-
pared from amino acids, as artificial receptors for chiral molecular
recognition.7 Herein, we wish to report on the preparation of new
chiral imidazolium salts and their investigation as CSRs using the
Mosher salt as the standard guest. In addition some of the imidazo-
lium salts that presented 5–11 can be qualified as CILs.8
The first step of the synthesis was the preparation of the enan-
tiopure imidazole rings derived from L-amino acids, which were
2. Results and discussion
used as the precursors of the desired final chiral imidazolium salts.
For this purpose we followed the procedure described by Bao
et al.8c The general synthetic route is outlined in Scheme 1. Sodium
Taking this into account, we decided to search for a family of
versatile and powerful non-covalent chiral shift reagents that
could be easily synthesized from the chiral pool. In this regard,
we used natural amino acids as the starting chiral materials and io-
L
-2-(1-imidazolyl) alkanoic acids 1 were obtained from
acids having different side chains. In our case, -valine, -isoleucine,
and -phenylalanine were used as the starting materials
L-amino
L
L
L
(R = CH(CH3)2, CH2CH(CH3)2, and CH2Ph). The respective ethyl es-
ters 3b and 3c were prepared from Phe and Val using anhydrous
EtOH and HCl.9 On the other hand, the methyl esters derived from
* Corresponding authors. Tel.: +34 964728239; fax: +34 964728214 (S.V.L.).
E-mail address: luiss@qio.uji.es (S.V. Luis).
0957-4166/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2009.03.028

1000
B. Altava et al. / Tetrahedron: Asymmetry 20 (2009) 999–1003
R
OMe
1) HCl
N
N
2) SOCl2/MeOH
O
2
2a, R = CH2CH(CH3)2
L-aa, NH3
R
(Yield 75%)
CH2O +
NaOH (aq)
2b, R = CH2Ph
(Yield 65%)
ONa
N
N
º
CHO-CHO
50 C
O
1a-c
a, R = CH2CH(CH3)2
(Yield 99%)
R
b, R = CH2Ph
(Yield 99%)
HCl/EtOH
OEt
N
N
c, R = CH(CH3)2
(Yield 99%)
O
3
3b, R=CH2Ph (Yield 33%)
3c, R = CH(CH3)3 (Yield 84%)
R
R
PhMgCl/THF
Br
ArCH2Br
OH
OH
N
N
N
N
Ph Ph
Ar
Ph Ph
4 a-c
5-6
a, R = CH2CH(CH3)2 (Yield 40%)
b, R = CH2Ph (Yield 42%)
5a, R = CH2CH(CH3)2, Ar = Ph (Yield 90%)
5b, R = CH2Ph, Ar = Ph (Yield 73%)
5c, R = CH(CH3)2, Ar = Ph (Yield 96%)
6b R = CH2Ph, Ar = Nf (Yield 92%)
6c R = CH(CH3)2, Ar = Nf (Yield 94%)
c, R = CH(CH3)2 (Yield 43%)
R
7a Ar = Ph, R= CH2CH(CH3)3, X = SbF6 (Yield 96.7%)
7b Ar = Ph, R=CH2Ph, X = SbF6 (Yield 92.9%)
8b Ar = Ph, R=CH2Ph, X = N(Tf)2 (84%) (Yield 84%)
8c Ar = Ph, R = CH(CH3)3, X = N(Tf)2. (Yield 73%)
9b Ar = Nf, R=CH2Ph, X = N(Tf)2 (Yield 76%)
9c Ar = Nf, R = CH(CH3)3, X = N(Tf)2 (Yield 80%)
KSbF6
X
OH
N
N
or LiNTf2
Ar
Ph Ph
7-9
Scheme 1. Synthesis of imidazolium-based salts.
L-isoleucine 2a and L-phenylalanine 2b were prepared by refluxing
(S) (R)
1a and 1b, respectively, in a mixture of anhydrous MeOH and SOCl2
based on known procedures described for the preparation of esters
of amino acids.9 The corresponding alcohols 4 were prepared by
addition of an excess of PhMgCl to compounds 2 and 3 in dry
THF at reflux in good yields.9 Imidazolium salts 5–6 were obtained
by reaction of 4 with the corresponding bromides in THF. Yields for
quaternization were good (80–90%). Finally the desired products
7–9 were prepared by anion metathesis of 5–6 with KSbF6 or
LiNTf2. The chiral imidazolium salts 7–9 prepared were white sol-
ids with melting points ranging from 70 to 120 °C. The structures
of the new chiral receptors were characterized by 1H NMR, 13C
NMR, IR, MS, and elemental analysis.10
3.90 3.70 3.50 3.30 3.10
3.60
3.55
Figure 2. Partial 1H NMR spectra (CD3CN, 500 MHz) of (a) potassium salt of Mosher
acid. (b) Potassium salt of Mosher acid after the addition of 3 equiv of 8b showing
the splitting of the signal corresponding to the OMe group attached to Ca. The
signals for the enantiomers were assigned by adding a known amount of one
enantiomer to the racemic solution.
1H NMR spectroscopy was used to investigate the chiral recog-
nition ability of compounds 5b and 7–9, with racemic chiral car-
boxylic acids as the guests. For the initial studies, the racemate
of the Mosher acid salt was chosen as the guest and 3:1 mixtures
of 5b, 7–9, and the potassium salt of the Mosher acid were exam-
ined.11 The signal of the methoxy group of this guest is a sharp sin-
glet at 3.56 ppm in CD3CN and does not overlap with the peaks of
the other proton signals in the 1H NMR spectra either for the host
or for the guest. Therefore, it is an ideal probe for chiral discrimina-
tion. As shown in Figure 2, upon addition of the imidazolium
receptors, the signal of the methoxy protons of the Mosher acid
was upfield shifted and splits into two peaks due to the formation
of two diastereotopic complexes between the CSRs and the enanti-
omers of the guest, which confirms that chiral recognition has oc-
curred. When binding 8b, chemical shift values of the (R)- and (S)-
Mosher acid salt exhibit 0.016 and 0.041 ppm upfield shifts,
respectively. These results suggest a different chemical environ-
ment for the two enantiomers of the Mosher acid, and that host-
guest instantaneous complexes had been formed.
The determination of the stoichiometry of the species formed is
important to analyze the structure of the complexes. Therefore, the
stoichiometric ratios of the host–guest complexes were investi-
gated by the Job plot method.12 The Job plot for the complexation
of 8b with the (R)- and (S)-potassium salts of the Mosher acid is
illustrated in Figure 3, where XH is the molar fraction of 8b and
XG is the molar fraction of the potassium salt of the Mosher acid.
The total concentration of the two compounds was kept constant
(10 mM) and
Dd is the chemical shift change of the C2 imidazolium
proton signal of 8b. The plot exhibits a maximum at X = 0.5, indi-
cating 1:1 complexation.
To evaluate the chiral discrimination abilities of the different
chiral imidazolium salts 5b and 7–9, we measured the NMR spec-
tra for the 3:1 mixtures of the corresponding imidazolium salt and
the potassium salt of the Mosher acid in CD3CN. Some results are
summarized in Table 1 where shifts of the methyl H and F nuclei
for the potassium salt of the Mosher acid are shown. Chemical shift

B. Altava et al. / Tetrahedron: Asymmetry 20 (2009) 999–1003
1001
The global minima from this conformational search were opti-
mized in a DFT study with both (R)- and (S)-Mosher acids and host
8b.14 The optimized structures are shown in Figure 4. As can be
seen, both diastereomeric complexes show hydrogen bonding be-
tween hydroxy and carboxylate groups, but only one diastereo-
meric complex displays a hydrogen bond between the C2 proton
of the imidazolium ring and the carboxylate group. This hydrogen
bond seems to allow the formation of more stable complexes
(DE = 1.2 kcal/mol). This is in accordance with the experimental re-
sults derived from the 1:1 diastereomeric complexes between 8b
and the enantiopure potassium salt of Mosher acid (see Table 2).
This interaction model may explain why host 8b can discriminate
both enantiomers of Mosher acid as guest.
Figure 3. Job plot of 8b with (R)- and (S)-potassium salt of the Mosher acid. Total
concentration of 10 ꢁ 10ꢀ3 M.
Table 1
Selected 1H and 19F chemical shift nonequivalences of the racemic potassium salt of
Mosher acid in the presence of imidazolium salts 5b and 7–9 by NMR (500 MHz) in
CD3CN at 30 °C.
Entry
Hosta
Ar
X
D
db
DDdc (ppm)
DDdd (ppm)
1
2
3
4
5
6
7
7a
7b
5b
8b
9b
8c
9c
Phenyl
Phenyl
Phenyl
Phenyl
Naphthyl
Phenyl
Naphthyl
SbF6
SbF6
Br
NTf2
NTf2
NTf2
NTf2
0.011
0.028
0.012
0.026
0.035
0.015
ꢀ0.050
0.008
0.017
0.019
0.026
0.024
0
0
0
0
0.023
0.032
0
Figure 4. Optimized structure obtained by DFT search for the diastereomeric
complexes between 5c and potassium salt of Mosher acid.
0
0
a
All samples were prepared by mixing 1 equiv of racemic potassium Mosher salt
(0.01 M in CD3CN) and 3 equiv of chiral host (0.01 M in CD3CN) in NMR tubes.
Table 2
b
Averaged between signals from both enantiomers.
Association constants (Ka), Gibbs free energy changes (ꢀ
D
Go), enantioselectivity
c
1H chemical shift nonequivalences of methyl protons of the potassium salt of
Ka(S)/Ka(R)), or DDGo calculated from ꢀ
(R)-Mosher salt in CD3CN at 30 °C.
DGo for the complexation of 8b with (S)- or
Mosher acid.
d
19F chemical shift nonequivalences of the potassium salt of Mosher acid.
Entry Guesta Ka (mol/l)
Ka(S)/Ka(R)
ꢀ
D
Go (kcal/mol) DDGo (kcal/mol)
1
2
3
(R)
(S)
16.37 2.04
2.26 1.65
1.68
0.49
1.19
nonequivalences were observed in many cases. Chiral imidazolium
7.24
salts derived from L-phenylalanine 8b and 9b showed to be the
a
Concentration of host 0.01 M.
best shift reagents, with 1H chemical shift nonequivalences of
0.026 ppm for the methylic protons. However, only 1H chemical
shift nonequivalences of 0.008 pm were obtained when imidazoli-
um salts derived from leucine 7a were used as CSRs (entry 1) and
no chiral recognition was observed for imidazolium salts derived
The binding constants (Ka) for the association of 8b for the (R)-
and (S)-Mosher salt enantiomers were determined by NMR titra-
tions, assuming a 1:1 complexation. The Ka values were calculated
by means of a nonlinear least-squares method applied to the
downfield shift of the C2 imidazolium proton signal observed upon
addition of the guest, based on the Benesi–Hildebrand equation.15
from L-valine (entries 6 and 7).
On the other hand, when we studied the influence of the anion
of the starting chiral imidazolium salt for the phenylalanine deriv-
atives 5b, 7b, and 8b, we observed better shift nonequivalences for
soft anions such as NTf2, in particular for 19F signals (entry 4). Fi-
nally, the same chiral discrimination ability was found for com-
pounds 8b and 9b (entries 4 and 5). This result suggests the
Association constants (Ka) and free energy changes (ꢀ
DGo) are
shown in Table 2. The (R)-Mosher salt enantiomer has an associa-
tion constant seven times higher than the (S)-enantiomer. Thus,
the (R)-Mosher salt/8b complex is 1.19 kcal/mol more stable than
the (S)-Mosher salt/8b complex (entry 1).
absence of a
p–p interaction in the diastereomeric complexes
Finally, we have also demonstrated the practical applicability of
receptor 8b for the measurement of the ee of carboxylate salts,
using the Mosher acid salt as a model compound. Samples contain-
ing different proportions of both enantiomers of the Mosher acid
salt were prepared and analyzed with 8b as a CSR (Fig. 5), render-
ing an excellent linear response (R2 = 0.9992).
involving the benzylic or naphthylic moiety bound to the second
nitrogen atom of the imidazolium ring.
Considering the results obtained, and to understand the origin
of the discrimination, we performed a molecular modeling study
for the complex 8b/Mosher acid. Initially, a Monte Carlo conforma-
tional search using the conformer distribution option available in
SPARTAN’04 was used.13 With this option, an exhaustive Monte Carlo
search without constraints was performed for every structure. The
torsion angles were randomly varied and the structures obtained
were fully optimized using the MMFF. Thus, 100 minima of energy
within an energy gap of 10 kcal/mol were generated. When study-
ing the different structures derived from the conformational study,
3. Conclusion
In conclusion, we have designed and synthesized a new family
of CSRs based on imidazolium salts derived from natural amino
acids. They are efficient for discrimination of the potassium salt
of the Mosher acid by 1H NMR spectroscopy. The formation of dia-
stereomeric complexes is fast and quantitative, making possible
we observed the absence of any
p–p interaction in the diastereo-
meric structures, in accordance with the experimental evidence.

1002
B. Altava et al. / Tetrahedron: Asymmetry 20 (2009) 999–1003
7. (a) Plaquevent, J.-C.; Levillain, J.; Guillen, F.; Malhiac, C.; Gaumont, A.-C. Chem.
100
80
60
40
20
0
Rev. 2008, 108, 5035–5060; (b) Su, X.; Luo, K.; Xiang, Q.; Lan, J.; Xie, R. Chirality
2008.
8. (a) Baudequin, C.; Brégeon, D.; Levillain, J.; Guillen, F.; Plaquevent, J.-C.;
Gaumont, A.-C. Tetrahedron: Asymmetry 2005, 16, 3921–3945; (b)
Wasserscheid, P.; Welton, T. Ionic liquids in Synthesis; Willey-VCH:
Weinheim, 2003; (c) Baudequin, C.; Baudoux, J.; Levillain, J.; Cahard, D.;
Gaumont, A.-C.; Plaquevent, J.-C. Tetrahedron: Asymmetry 2003, 14, 3081–
3093; (d) Bao, W.; Wang, Z.; Li, Y. J. Org. Chem. 2003, 68, 591–593.
9. (a) Luis, S. V.; Altava, B.; Burguete, M. I.; Collado, M.; Escorihuela, J.;
´
Garcia-Verdugo, E.; Vicent, M. J.; Martens, J. Ind. Eng. Chem. Res. 2003, 42,
´
5977–5982; (b) Burguete, M. I.; Collado, M.; Garcia-Verdugo, E.; Vicent, M.
J.; Luis, S. V.; Von Keyserling, N. G.; Martens, J. Tetrahedron 2003, 59,
´
1797–1804; (c) Altava, B.; Burguete, M. I.; Garcia-Verdugo, E.; Luis, S. V.;
Pozo, O.; Salvador, R. V. Eur. J. Org. Chem. 1999, 2263–2267; (d) Altava, B.;
Burguete, M. I.; Collado, M.; Luis, S. V.; Pozo, O.; Salvador, R. Anal. Quím.,
Int. Ed. 1997, 93, 260–266.
0
20
40
60
80
100
10. Characterization of the imidazolium salt derivatives 7–9. Compound 7a: White
solid. Mp = 70 °C; ½a D20
ꢂ
¼ þ99:8 c 0.009, CH3OH). 1H NMR (300 MHz, CD3OD) d
ee prepared
(ppm): 0.85 (d, J = 6.5 Hz, 3H), 1.04 (d, J = 6.6, 3H), 1.25–1.41 (m, 1H), 1.64–1.76
(ddd, J = 14.9, 10.1 and 1.7 Hz, 1H), 2.09–2.22 (m, 1H), 5.21(d, 1H, J = 14.8 Hz),
5.28 (d, 1H, J = 14.8 Hz), 5.44 (dd, J = 11.9 and 1.5 Hz, 1H), 7.01–7.07 (m, 3H),
7.11–7.15 (m, 2H), 7.23–7.44 (m, 9H), 7.50 (s, 1H), 7.60 (d, J = 8 Hz, 2H), 8.88 (s,
1H). 13C NMR d (ppm): 20.5, 22.6, 25.1, 38.4, 52.8, 67.3, 79.6, 121.3, 125.0,
126.0, 126.9, 127.5, 128.1, 128.1, 128.5, 129.0, 129.2, 134.1, 136.1, 143.8, 143.8.
IR (KBr): 3547, 3158, 2961, 2873, 1552, 1496, 1449, 1154, 1063, 749, 703,
662 cmꢀ1. MS (ESI+, m/z): 411.2 [M+, 100%], (ESIꢀ, m/z): 234.9 [SbF6ꢀ, 100%].
Anal. Calcd (%) for C28H31F6N2OSb: C, 51.95; H, 4.83; N, 4.33. Found: C, 52.39;
Figure 5. Correlation between theoretical and observed ee values obtained by
500 MHz 1H NMR titrations of enantiomerically enriched mixtures of the Mosher
acid salt using 8b as CSR.
the analysis in situ in a 500 MHz NMR spectrometer. Moreover,
interaction between receptor and substrate is non-covalent, and
the receptor can be separated and recovered by a simple acid
extraction procedure. Further studies to improve the receptor
structure and for the application to guests of biological and medic-
inal relevance are in progress.
H, 5.62; N, 4.27. Compound 7b: White solid. Mp = 105–111 °C; ½a 2D0
¼ þ35 (c
ꢂ
0.010, CH3OH). 1H NMR (300 MHz, CD3OD) d (ppm): 3.26–3.32 (m, 2H), 5.05 (d,
J = 14.8 Hz, 1H), 5.11 (d, J = 14.8 Hz, 1H), 5.63–5.76 (m, 1H), 6.93–7.23 (m,
12H), 7.29–7.41 (m, 6H), 7.47 (dd, J = 7.7 and 7.4 Hz, 2H), 7.81 (d, J = 7.6 Hz,
2H), 8.76 (s, 1H). 13C NMR d (ppm): 36.0, 52.6, 70.5, 79.4, 121.2, 123.7, 125.0,
125.9, 127.1, 127.3, 127.9, 128.2, 128.7, 128.8, 128.9, 129.0, 129.2, 134.0, 136.0,
136.4, 143.6, 143.8. IR (KBr): 3547, 3155, 3064, 2958, 1551, 1496, 1450, 1149,
1064, 745, 703, 656 cmꢀ1. MS (ESI+, m/z): 445.4 [M+, 100%], (ESIꢀ, m/z): 234.8
[SbF6ꢀ, 100%]. Anal. Calcd (%) for C31H29F6N2OSb: C, 54.65; H, 4.29; N, 4.11.
Found: C, 55.03; H, 5.01; N, 4.10. Compound 8b: White solid. Mp = 60–63 °C;
Acknowledgments
½
a 2D0
ꢂ
¼ þ41:4 (c 0.004, CH3OH). 1H NMR (500 MHz, CD3CN) d (ppm): 3.21–3.36
Financial support from the Spanish M.C.I. (CTQ2008-04412) and
Fundació Bancaixa-UJI (P1-1A2007-09) is acknowledged. J.E.
thanks UJI for a contract under the program: Pla de Promoció de
la Investigació de la Universitat Jaume I.
(m, 2H), 5.14 (s, 2H), 5.60 (dd, J = 11.7 and 3.0 Hz, 1H), 6.96–7.01 (m, 2H), 7.02
(s, 1H), 7.10–7.19 (m, 5H), 7.21 (s, 1H), 7.24–7.27 (m, 3H), 7.35 (d, J = 7.0 Hz,
2H), 7.73–7.78 (m, 2H), 7.39–7.43 (m, 4H), 7.54 (dd, J = 7.8 and 7.5 Hz, 2H),
7.75 (d, J = 7.7 Hz, 2H), 8.47 (s, 1H). 13C NMR d (ppm): 36.0, 53.2, 70.4, 79.9,
116.4, 118.9, 120.8, 121.5, 123.6, 124.0, 125.0, 125.5, 127.5, 127.7, 128.1, 128.3,
128.8, 129.2, 129.5, 129.5, 132.2, 135.7, 136.2, 142.6, 143.0. IR (KBr): 3504,
3146, 3069, 3033, 1551, 1497, 1450, 1351, 1199, 1135, 1058, 742, 701, 66ꢀ2,
References
615, 570, 512 cmꢀ1. MS (ESI+, m/z): 445.4 [M+, 100%], (ESIꢀ, m/z): 280.2 [NTf2
,
100%]. Anal. Calcd (%) for C33H29F6N3O5S2: C, 54.62; H, 4.03; N, 5.79. Found: C,
54.32; H, 3.98; N, 5.72. Compound 8c: White solid. Mp = 110 °C; ½a D20
¼ þ46:9
ꢂ
1. (a) Patrick, G. L. An Introduction to Medicinal Chemistry; Oxford University
Press: New York, 2005; (b) Bladon, C. Pharmaceutical Chemistry: Therapeutic
Aspects of Biomacromolecules; Wiley: Chichester, England, 2002.
2. (a) Wenzel, T. J. Discrimination of Chiral Compounds Using NMR Spectroscopy;
Wiley: New Jersey, 2007; (b) Vespalec, R.; Bocek, P. Chem. Rev. 2000, 100,
3715–3754; (c) Schuric, V.; Nowotny, A. P. Angew. Chem., Int. Ed. 1990, 29,
939–957; (d) Pirkle, W. H.; Bocek, P. Chem. Rev. 1989, 89, 347–362.
3. (a) Uccello-Barretta, G.; Balzano, F.; Salvadori, P. Curr. Pharm. Des. 2006, 12,
4023–4045; (b) Uccello-Barretta, G.; Balzano, F.; Sicoli, G.; Scarselli, A.;
Salvadori, P. Eur. J. Org. Chem. 2005, 5349–5355; (c) Uccello-Barretta, G.;
Balzano, F.; Martinelli, J.; Berni, M. G.; Villani, C.; Gasparrini, F. Tetrahedron:
Asymmetry 2005, 16, 3746–3751; (d) Wenzel, T. J.; Wilcox, J. D. Chirality 2003,
15, 256–270; (e) Parker, D. Chem. Rev. 1991, 91, 1441–1457.
(c 0.011, CH3OH). 1H NMR (500 MHz, CD3Cl) d (ppm): 0.90 (d, J = 6.9 Hz, 3H),
0.95 (d, J = 6.7 Hz, 3H), 2.44–2.56 (m, 1H), 3.26 (br, 1H, OH), 5.12 (d, J = 14.8 Hz,
1H), 5.25 (d, J = 14.8 Hz, 1H), 5.48 (d, J = 5.8 Hz, 1H), 6.81 (s, 1H), 6.96 (d,
J = 7.4 Hz 2H), 7.05 (m, 1H), 7.13 (dd, J = 7.7 and 7.7 Hz, 2H), 7.27–7.43 (m, 8H),
7.50 (s, 1H), 7.63 (d, J = 8.4 Hz, 2H), 9.11 (s, 1H). 13C NMR d (ppm): 19.2, 22.2,
29.8, 53.4, 72.4, 81.4, 118.9, 120.5, 121.4, 123.6, 124.7, 124.9, 127.5, 128.2,
128.3, 128.8, 129.4, 129.6, 129.6, 132.8, 137.7, 143.4, 143.6. IR (KBr): 3506,
3138, 3074, 2975, 1555, 1450, 1346, 1184, 1128, 1056, 741, 704, 640, 593,
569 cmꢀ1. MS (ESI+, m/z): 397.4 [M+, 100%], (ESIꢀ, m/z): 280.2 [NTf2ꢀ, 100%].
Anal. Calcd (%) for C29H29F6N3O5S2: C, 51.40; H, 4.31; N, 6.20. Found: C, 52.17;
H, 5.10; N, 6.24. Compound 9b: White solid. Mp = 120 °C; ½a D20
¼ þ27:4 c 0.005,
ꢂ
CH3OH). 1H NMR (500 MHz, CD3Cl) d ppm: 3.24 (dd, J = 14.8 and 12.2 Hz, 1H)
3.38 (dd, J = 14.9 and 1.9 Hz, 1H), 3.68 (br, 1H, OH), 5.23 (s, 2H), 5.71 (dd,
J = 11.8 and 2.4 Hz, 1H), 6.73 (s, 1H), 6.93 (d, J = 8.5 Hz, 1H), 7.02 (dd, J = 7.4 and
7.3 Hz, 1H), 7.06 (d, J = 7.4 Hz, 2H), 7.10–7.20 (m, 6H), 7.34–7.40 (m, 3H), 7.48
(dd, J = 7.8 and 7.5 Hz, 2H), 6.54–7.58 (m, 2H), 7.59 (s, 1H), 7.69 (d, J = 8.1 Hz,
2H), 7.79–7.87 (m, 3H), 8.97 (s, 1H). d (ppm): 13C NMR d (ppm): 36.1, 53.6, 70.5,
79.9, 118.9, 120.7, 121.4, 123.3, 124.9, 125.0, 125.4, 127.2, 127.4, 127.5, 127.7,
128.0, 128.2, 128.3, 128.4, 128.7, 128.8, 129.2, 129.5, 129.7, 130.1, 133.3, 133.6,
135.6, 136.5, 142.5, 142.8. IR (KBr): 3512, 3149, 3066, 3025, 1352, 1187, 1128,
1051, 746, 699, 617, 599, 569 cmꢀ1. MS (ESI+, m/z): 495.2 [M+, 100%], (ESIꢀ, m/
z): 280.1 [NTf2ꢀ, 100%]. Anal. Calcd (%) for C37H31F6N3O5S2: C, 57.28; H, 4.03; N,
5.42. Found: 57.98; H, 4.85; N, 5.58. Compound 9c: White solid. Mp = 65–
4. (a) Wang, W.; Shen, X.; Ma, F.; Li, Z.; Zhang, C. Tetrahedron: Asymmetry 2008,
´
19, 1103–1199; (b) Gonza´lez-Sabin, J.; Alfonso, I.; Rebolledo, F.; Gotor, V.
Tetrahedron 2008, 64, 7709–7717; (c) Ema, T.; Tanida, D.; Sakai, T. J. Am. Chem.
Soc. 2007, 129, 10591–10596; (d) Wang, W.; Ma, F.; Shen, X.; Zhang, C.
Tetrahedron: Asymmetry 2007, 18, 832–837; (e) Ma, F.; Ai, L.; Shen, X.; Zhang,
C. Org. Lett. 2007, 9, 125–127; (f) Li, B.; Yang, X.; Wu, X.; Luo, Z.; Zhong, C.; Fu,
E. Supramol. Chem. 2006, 18, 507–513; (g) Ema, T.; Tanida, D.; Sakai, T. Org.
Lett. 2006, 8, 3773–3776; (h) Yang, D.; Li, X.; Fan, Y.-F.; Zhang, D.-W. J. Am.
Chem. Soc. 2005, 127, 7966–7967; (i) Breccia, P.; Gool, M. V.; Pérez-Fernández,
R.; Martín-Santamaría, S.; Gago, F.; Prados, P.; de Mendoza, J. J. Am. Chem. Soc.
2003, 125, 8270–8284; (j) Baragana, B.; Blackburn, A. G.; Breccia, P.; Davis, A.
P.; de Mendoza, J.; Padrón-Carrillo, J. M.; Prados, P.; Riedner, J.; de Vries, J. G.
Chem. Eur. J. 2002, 8, 2931–2936; (k) Lawless, L. J.; Blackburn, A. G.; Ayling, A.
J.; Pérez-Payán, M. N.; Davis, A. P. J. Chem. Soc., Perkin Trans. 1 2001, 1329–
1341.
69 °C; ½a D20
ꢂ
¼ þ74:7 c 0.011, CH3OH). 1H NMR (500 MHz, CD3Cl) d (ppm): 0.91
(d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.7 Hz, 3H), 2.45–2.54 (m, 1H), 3.19 (br, 1H, OH),
5.26 (d, J = 14.6 Hz, 1H), 5.42 (d, J = 14.7 Hz, 1H), 5.50 (d, J = 5.8 Hz, 1H), 6.84 (s,
1H), 6.93 (dd, J = 7.4 and 7.1 Hz, 1H), 6.98 (d, J = 8.4 Hz, 1H), 7.08 (dd, J = 7.8
and 7.4 Hz, 2H), 7.27–7.33 (m, 1H), 7.37 (d, J = 8.2 Hz, 2H), 7.41 (dd, J = 7.2 and
7.5 Hz, 2H), 7.5 (s, 1H), 7.54–7.58 (m, 2H), 7.61 (s, 1H), 7.64 (d, J = 6.8 Hz, 2H),
7.80–7.88 (m, 3H), 9.20 (s, 1H). 13C NMR d (ppm): 20.0, 22.2, 29.8, 72.7, 81.2,
118.9, 120.7, 121.5, 124.2, 124.6, 125.0, 125.0, 127.2, 127.3, 127.4, 128.1, 128.3,
128.7, 129.2, 130.2, 133.4, 133.6, 136.9, 143.4, 143.7. IR (KBr): 3512, 3149,
5. (a) Zheng, Y.-S.; Zhang, C. Org. Lett. 2004, 6, 1189–1192; (b) Yang, X.-M.; Wu, X.-
J.; Fang, M.-H.; Yuan, Q.; Fu, E.-Q. Tetrahedron: Asymmetry 2004, 15, 2491–2497.
6. (a) Patil, M. L.; Rao, C. V. L.; Yonezawa, K.; Takizawa, S.; Onitsuka, K.; Sasai, H.
Org. Lett. 2006, 8, 227–230; (b) Ishida, Y.; Sasaki, D.; Miyauchi, H.; Saigo, K.
Tetrahedron Lett. 2006, 46, 7973–7976; (c) Luo, S.-P.; Xu, D.-Q.; Yue, H.-D.;
Wang, L.-P.; Yang, W.-L.; Xu, Z.-Y. Tetrahedron: Asymmetry 2006, 17, 2028–
2033; (d) Levillain, J.; Dubant, G.; Abrunhosa, I.; Gulea, M.; Gaumont, A.-C.
Chem. Commun. 2003, 2914–2915; (e) Wasserscheid, P.; Bösmann, A.; Bolm, C.
Chem. Commun. 2002, 200–201.
3066, 2972, 1551, 1446, 1346, 1187, 1128, 1051, 740, 704, 611, 599, 569 cmꢀ1
.
MS (ESI+, m/z): 447.4 [M+, 100%], (ESIꢀ, m/z): 280.2 [NTf2ꢀ, 100%]. Anal. Calcd
(%) for C33H31F6N3O5S2 C, 54.46; H, 4.29; N, 5.77. Found: C, 54.95, H, 4.56; N,
5.75.

B. Altava et al. / Tetrahedron: Asymmetry 20 (2009) 999–1003
1003
11. Clavier, H.; Boulanger, L.; Audic, N.; Toupet, L.; Mauduit, M.; Guillemin, J.-C..
Chem. Commun. 2004, 1224–1225.
12. (a) Gil, V. M. S.; Oliveira, N. C. J. Chem. Ed. 1990, 67, 473–478; (b) Job, P. Ann.
Chim. Fr. 1928, 9, 113–203.
13. Wavefunction, Inc. Irvine, CA. For MMFF force field calculations, see:
Halgren, T. A. J. Comput. Chem. 1996, 17, 490–519 and following papers in
this issue.
Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.;
Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.;
Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.;
Clifford, S.; Closlowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.;
Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.;
Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.;
Wong, M. W.; Gonzalez, C.; and Pople, J. A.; GAUSSIAN 03, Revision D.01, Gaussian,
Inc., Wallingford, CT, 2004. Structures were computed using DFT with the
nonlocal hybrid Becke’s three-parameter exchange functional (B3LYP) 6-31G
(d) basis set f atoms of the GAUSSIAN 03 software package.
14. Frisch, M.J.
; Trucks, G.W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennuccl, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.;
Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.;
15. (a) Fielding, L. Tetrahedron 2000, 56, 6151–6170; (b) Connors, K. A. Binding
Constants The Measurement of Molecular Complex Stability; Wiley-Interscience:
New York, 1987.