Novel carbohydrate-based chiral ammonium ionic liquids derived from isomannide

Article abstract of DOI:10.1016/j.tetasy.2008.02.009

This report describes the synthesis and characterization of novel carbohydrate-based chiral ammonium ionic liquids using isomannide as a biorenewable substrate. The diastereomeric interactions of these chiral ammonium ionic liquids with racemic Mosher's a

Full text of DOI:10.1016/j.tetasy.2008.02.009

Available online at www.sciencedirect.com
Tetrahedron: Asymmetry 19 (2008) 664–671
Novel carbohydrate-based chiral ammonium ionic liquids
derived from isomannide
Vineet Kumar,a,b, Cao Pei,b Carl E. Olsen,c Susan J. C. Schaffer,d Virinder S. Parmarb,*
¨
and Sanjay V. Malhotraa,*,
aDepartment of Chemistry and Environmental Science, New Jersey Institute of Technology, University Heights, Newark, NJ 07102, USA
bBioorganic Laboratory, Department of Chemistry, University of Delhi, Delhi 110 007, India
cUniversity of Copenhagen, Faculty of Life Sciences, Department of Natural Sciences, DK-1871 Frederiksberg C, Denmark
dDepartment of Chemistry, Building 207, Technical University of Denmark, DK-2800 Lyngby, Denmark
Received 4 December 2007; accepted 4 February 2008
Abstract—This report describes the synthesis and characterization of novel carbohydrate-based chiral ammonium ionic liquids using iso-
mannide as a biorenewable substrate. The diastereomeric interactions of these chiral ammonium ionic liquids with racemic Mosher’s acid
salt have been studied using NMR, which indicates their participation in chiral discrimination and shows their potential applications in
chiral resolution.
Ó 2008 Elsevier Ltd. All rights reserved.
1. Introduction
pounds under milder conditions.2 In addition to their
utility in organic synthesis, ILs have been studied in bio-
processing operations,3 as electrolytes in electrochemistry,4
in gas separations,5 in liquid–liquid extractions,6 and as
heat-transfer fluids.7
Over the past decade, ionic liquids (ILs) have attracted
considerable attention as promising materials for a variety
of applications.1 Ionic liquids (salts having a melting point
below 100 °C) possess the advantages such as negligible
vapor pressure, high thermal stability, and recyclability,
which makes them the prominent candidate to replace con-
ventional volatile organic solvents (VOC’s). The possibili-
ties of structural variation offer a flexibility to design the
most idealized solvent suitable for the needs of any partic-
ular process. Apart from tunable physical and chemical
properties of ionic liquids, their immiscibility with various
organic solvents enables the biphasic separation of the de-
sired products and recycling of expensive catalysts.1 Fur-
thermore, their ability to dissolve complex molecules such
as nucleosides and amino acids allows the chemists to per-
form chemo- and enantioselective reactions on these com-
Important progress over the past few years with the devel-
opment of chiral ionic liquids (CILs) has given a new
dimension to ionic liquid-based research.8 Though the
CILs are at an early stage of development, they have
shown promising results in asymmetric synthesis,9 stereo-
selective polymerization,10 chiral chromatography,11
liquid crystals,12 chiral resolution, and as NMR shift
reagents.13 One of the efficient and convenient method
to synthesize CILs uses substrates derived from a chiral
pool, especially from biorenewable sources. Chiral precur-
sors viz. (ꢀ)-ephedrine,13a,14 (S)-nicotine,15 (ꢀ)-men-
thol,9b,10c,16 (+)-pinocarvone,17 and amino acids13b,18
have been used for the synthesis of CILs. Previously we
reported the first synthesis of CILs based on a-pinene
and their applications as co-solvents for the enantioselec-
tive addition of diethylzinc to enones.9f Carbohydrate-
based ligands have played a significant role in enantiose-
lective organic transformations.19 However, the synthesis
of CILs from carbohydrate-based substrates is yet to be
explored.
*
Corresponding authors. Tel./fax: +91 11 27667206 (V.S.P.); tel.: +1 301
846 5141; fax: +1 301 846 7239 (S.V.M.); e-mail addresses:
virparmar@gmail.com; malhotrasa@mail.nih.gov
Present address: Laboratory of Synthetic Chemistry, SAIC-Frederick
Inc, National Cancer Institute at Frederick, 1050 Boyles Street,
Frederick, MD 21702, United States.
0957-4166/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2008.02.009

V. Kumar et al. / Tetrahedron: Asymmetry 19 (2008) 664–671
665
Isomannide 1 and isosorbide 2 are commercially available
TsO
O
HO
O
H
H
HO
4
H
H
H
chiral dianhydrohexitols (Fig. 1). They can be easily pre-
pared in enantiomerically pure form by double dehydra-
tion of sorbitol and mannitol, which are major
byproducts of the starch industry: Both are obtained in
large amounts as waste during the processing of corn oil.
These compounds have been used as starting materials
for the synthesis of biodegradable and high Tg polymers,20
pharmaceutically important compounds including vasodi-
lators and Xa-inhibitors,21 and as chiral ligands or as
phase-transfer catalysts in asymmetric synthesis.22 Surpris-
ingly however, despite their easy availability from a renew-
able and inexpensive source, there are very few examples of
their application as chiral auxillaries23 and in the synthesis
of CILs.24 We have recently completed the synthesis of
bis(ammonium) CILs derived from isomannide (Fig. 2)
and demonstrated their application as chiral shift re-
agents.25 Herein, we report our extended studies on the
synthesis of a new series of mono-ammonium CILs derived
from isomannide and their application for chiral
recognition.
TsCl, Pyridine,
O
O
CH2Cl2, 12 hrs, RT
O
7
+
5
3
O
1
8
OTs
OTs
H
OH
10
9
1
Scheme 1. Tosylation of isomannide.
which could be further subjected to anion exchange reac-
tions to make a series of chiral ionic liquids. D-Isomannide,
also known as (1R,4R,5R,8R)-2,6-dioxabicyclo [3.3.0] oc-
tan-4,8-diol 1 was first reacted with p-toulenesulfonyl chlo-
ride under basic medium using pyridine/CH2Cl2 (ꢁ1:3) as a
solvent to give monotosyl derivative 9 as the major product
and ditosyl derivative 10 as the minor product. The ditosyl
isomannide was utilized for the synthesis of bis(ammo-
nium) CILs (Fig. 2).25 The free hydroxyl group of monot-
osyl isomannide 9 was converted to its ethyl ether
derivative 11 by reaction with ethyl bromide under basic
conditions using tetrabutylammonium bromide (TBAB)
as a phase-transfer catalyst (Scheme 2). Subsequently, 11
was converted to amino ether 12 by heating with benzyl-
amine (in excess) at 180 °C.22a,26 As a result, the tosyloxy
group was removed as a salt of benzylamine. This is an
exclusive SN2 substitution causing complete inversion,
which was confirmed by comparing the coupling con-
stant between C-1H and C-8H of compounds 11
[J(H11, H8)cis = 4.5 Hz] and 12 [J(H1,H8)trans = 0 Hz] from
their H NMR spectrum. Due to this inversion of configu-
ration, the isomannide nucleus was converted to isosor-
bide. The sec-amine 12 was then directly quaternized to
its ammonium iodide salt 13 by treatment with methyl io-
dide using potassium carbonate as the base. The structure
and stereochemistry of 13 was established by 1H, 13C
NMR spectroscopy and further confirmed by anomalous
dispersion (Fig. 3). The chiral ammonium iodide salt 13
OH
O
OH
O
O
O
HO
OH
1
2
Figure 1. Isomannide 1 amd isosorbide 2.
O
CH3
CH3
H
+
CH2Ph
+
N
N
PhCH2
CH3
CH3
H
O
2X-
6: X = CF3COO
7: X = BF4
8: X = CF3SO3
3: X = I
4: X = Tf2N
5: X = PF6
Figure 2. Bis-ammonium CILs derived from isomannide.
EtO
O
HO
O
H
EtO
O
H
H
H
O
O
(ii)
(i)
O
2. Results and discussion
H
N
The substitution reaction of isosorbide gives three products
(two monosubstituted and one disubstituted) due to its
unsymmetrical stereochemistry, which makes the purifica-
tion and isolation of the products more tedious. Thus,
for our current study, we chose isomannide as the starting
material due to its preferential stereochemistry. Isoman-
nide is a symmetrical molecule with C2-axial symmetry
comprising of two cis-fused furan rings and two cis-ori-
ented hydroxyl groups with both the heterocyclic rings
and two hydroxyl groups in same plane. Substitution of
isomannide gives only two products, i.e., monosubstituted
major product and the sterically unfavorable disubstituted
as a minor product (Scheme 1).
H
OTs
OTs
H
12
9
11
(iii)
EtO
EtO
O
H
H
H
(iv)
O
O
O
H
+
N
+
N
I-
X-
13
17; X = BF4
14; X = (CF3SO2)2N
15; X = PF6
18; X = CF3SO3
16; X = CF3COO
Scheme 2. Synthesis of mono-ammonium CILs. Reagents and conditions:
(i) EtBr, TBAB, 50% KOH, CH2Cl2, rt; (ii) Benzylamine, 180 °C, 12 h; (iii)
MeI, K2CO3, CH3CN, rt; (iv) anion metathesis: AgX, H2O, 50 °C.
Our primary objective was to convert one of the hydroxyl
groups of isomannide to a quaternary ammonium salt,

666
V. Kumar et al. / Tetrahedron: Asymmetry 19 (2008) 664–671
of intermolecular contacts, which can raise their melting
points and viscosity. The high molecular weight of the cat-
ion of bis-ammonium salts in comparison with the cation
of the mono-ammonium salts could also contribute to high
melting points of bis-ammonium salts27 (except in the case
of [TfO] as an anion).
The anion also has a major effect on the physical properties
of ionic liquids including the melting point.27 There is a
very complex and poorly understood relationship between
the anion and cation size, degree of interaction (both ionic
and hydrogen bonding), packing, etc. that relates the phys-
ical properties of ionic liquids to their chemical structure.26
Ionic liquids with bulky and weakly coordinating anions
are known to have lower melting points. The Coulombic
interactions between cation and anion are also important.
In general, the lower the interaction between cation and an-
ion, the lower the melting point. These Coulombic interac-
tions can be minimized by diffusing the charge over several
atoms in a molecule.27,28 The [Tf2N] anion combines a
number of structural features to give the resultant salts
low melting points. This could be the reason that most of
the ionic liquids with a [Tf2N] anion are liquid at room
temperature. The charge on the [Tf2N] anion is particularly
diffused and spread through the S–N–S core and partially
to the trifluoromethane groups as well. Similar charge dif-
fusion is also present in [TFA] and [TfO] anions where the
negative charge is spread over O–C–O, and O–SO2 moie-
ties, respectively (Fig. 4). This diffusivity results in a de-
creased interaction between the cation and the anion.
Thus, in the case of both the mono-ammonium and bis-
ammonium ionic liquids, the salts with weakly coordinat-
ing anions, viz. [Tf2N], [TFA], and [TfO], which can
delocalize the charge through induction to highly electro-
negative fluorine atoms or by resonance, have lower melt-
ing points when compared to those having [I], [PF6], and
[BF4] as counter ions (Table 1).
Figure 3. X-ray crystal structure of the cationic part of CIL 13.à
Table 1. Melting point comparison of mono- and bis-ammonium CILs
Entry
Anion
Mono-ammonium
Bis-ammonium25
CILs
Mp (°C)
CILs
Mp (°C)
1
2
3
4
5
6
[I]
13
14
15
16
17
18
170
Oil
95
Oil
150
80
3
4
5
6
7
8
190
60
251
65
240
75
[Tf2N]
[PF6]
[TFA]
[BF4]
[TfO]
was used for anion exchange reactions to obtain other chi-
ral salts with different anions. The anion exchange reac-
tions were carried out in an aqueous medium.
The solubility of iodide salt 13 is low in water at room tem-
perature, therefore, reactions were carried out at 50–60 °C;
the iodide salt 13 was completely soluble at this tem-
perature. Thus, the desired mono-ammonium CILs 13–18
were synthesized following a simple and convenient meth-
odology involving simple functional group interconver-
sions followed by anion exchange (Scheme 2).
The melting point comparison of all the mono-ammonium
CILs and bis-ammonium CILs is given in Table 1. It has
been well reported in the literature that the ionic liquids
with unsymmetrical cations or anions have low melting
points in comparison to the ILs that have symmetrical cat-
ions or anions.27 Increasing symmetry of ions allows more
efficient packing in the crystal cells and provides high lat-
tice energy, resulting in an increase in the melting point.
Conversely, the loss of symmetry causes crystallographic
disorder and reduces the lattice energy, which results in
low melting points of ionic liquids with unsymmetrical cat-
ions. The bis-ammonium salts 3–8 consist of a highly sym-
metrical cation with C2-axial symmetry and identical
substituents. On the other hand, mono-ammonium salts
13–18 are completely unsymmetrical with a nucleus having
two different groups attached at the two ends of the mole-
cule. This could be one of the reasons that bis-ammonium
salts have high melting points when compared to those of
the mono-ammonium salts (Table 1). Generally, the ionic
liquids with a high molecular weight have a greater number
-
-
-
O
O
S
O
S
O
O
F3C
F3C
S
F3C
N
F3C
O
O
O
O
-
CF3SO3
[TfO]
CF3COO-
[TFA]
(CF3SO2)2N-
[Tf2N]
Figure 4. Delocalization of negative charge on [Tf2N], [TFA], and [TfO]
anions.
Having synthesized these chiral ionic liquids, we were inter-
ested in their utility for chiral induction. The enantiomeric
recognition ability of any chiral catalyst/promoter/solvent
is the most important property for their application in
asymmetric induction. We studied the chiral recognition
ability of these novel mono-ammonium CILs by investigat-
ing the diastereomeric interaction between the CILs and
racemic Mosher’s acid silver salt. Iodide salt 13 was dis-
solved in deuterated acetonitrile and stirred with racemic
Mosher’s acid silver salt. The AgI precipitate was filtered
off and the resulting solution containing Mosher’s acid
à The CIF files of X-ray data can be accessed through http://www.ccdc.
cam.ac.uk (deposition number CCDC 652067).

V. Kumar et al. / Tetrahedron: Asymmetry 19 (2008) 664–671
667
chiral ammonium salt A was probed by 19F NMR spectro-
10
9
8
7
6
5
4
3
2
1
0
scopy. The diastereomeric interactions between the chiral
ammonium cation and Mosher’s carboxylate resulted in
splitting of the CF3 signal (Fig. 5, spectrum (a)). When
the same NMR solution was mixed with 3.5 equiv of CIL
14, a remarkable increase in chemical shift value (Dd) of
CF3 signal was observed (Fig. 5, spectrum (b)).
EtO
H
0
0.2
0.4
0.6
0.8
1
CF3
MeO
O
COO-
IL Conc (mol/L)
*
O
Figure 6. Concn effect of CIL 14 on the Dd values of –CF3 signal of
racemic Mosher’s carboxylate.
H
+
N
Δδ = 9 Hz
Δδ = 3 Hz
A
–CF3 signals of racemic Mosher’s carboxylate was ob-
served when increasing the concentration of Chiral IL 14
from 0 to 0.81 mol/L.
a
b
3. Conclusion
-71.12
-71.20
-70.90
-71.00
In conclusion, we have synthesized a new series of mono-
ammonium CILs derived from isomannide, a carbohy-
drate-based biorenewable substrate. The effect of symme-
try, molecular weight and charge delocalization of cations
and anions on the melting points of these CILs has been
demonstrated. The enantiomeric recognition ability of
these CILs has been investigated by studying the diastereo-
meric interactions between CILs and racemic substrate
probed by NMR spectroscopy. These observations indicate
the potential of this new class of CILs in the resolution of
racemates, as chiral shift reagents and as chiral solvents/
catalysts in asymmetric synthesis. Further studies are in
progress in our laboratory.
Figure 5. 19F NMR signal of –CF3 of salt A (a) and salt A in the presence
of 3.5 equiv of CIL 14.
Our previous work9f and another report9e suggest that the
achiral anion may have some effect on the chiral discrimi-
nation induced by the CILs. This prompted us to investi-
gate the effect of anions on the diastereomeric
interactions between CILs and Mosher’s carboxylate. We
carried out similar 19F NMR experiments in the presence
of all other CILs (as done with [Tf2N]). The results are
compared with those of bis-ammonium CILs and summa-
rized in Table 2. These results prove the effect of the cation
and anion on the chiral discrimination ability of these
CILs, which is indicated by the enhancement in the magni-
tude of Dd values (Table 2).
4. Experimental
Melting points were determined on a Thomas Hoover Cap-
illary Melting Point instrument. The specific rotations were
measured on AUTOPOLÒ IV automatic polarimeter from
Rudolph Research Analytical. The 1H and 13C NMR spec-
tra were recorded on a Bruker ARX-300 spectrometer at
300 and at 75.5 MHz, respectively, using TMS as internal
standard. The 19F NMR spectra were recorded on a Bruker
ARX-300 spectrometer at 282.4 MHz using hexafluorobenz-
ene as reference. The chemical shift values are on d scale
and the coupling constants (J) are in Hertz. The high reso-
lution mass spectra were done on a microTOF-Q instru-
ment from Bruker Daltonics, Bermen and were recorded
with ESI in positive mode. The X-ray crystallography
was done on Bruker 2001 SAINT, SHELXTL, SMART, XCIF.
Bruker AXS, Inc., Madison, Wisconsin, USA. All the
chemicals used were purchased either from Aldrich Chem-
ical Co. or Fluka Chemicals Co., USA and used without
further purification. Analytical TLCs were performed on
pre-coated Merck Silica Gel 60F254 plates; the spots were
detected under UV light. Silica gel (100–200 mesh) was
used for column chromatography.
Table 2. Enhanced Dd values of –CF3 signals of rac-Mosher’s carboxylate
in the presence of mono- (3.5 equiv) and bis-ammonium (4.0 equiv) CILs
Entry
Anion
Mono-ammonium
Bis-ammonium25
CILs
Dd (Hz)
CILs
Dd (Hz)
1
2
3
4
5
6
[I]
13
14
15
16
17
18
7
9
8
5
5
9
3
4
5
6
7
8
9
23
21
8
17
15
[Tf2N]
[PF6]
[TFA]
[BF4]
[TfO]
The chemical shift induced by the CILs is highly dependent
on the concentration of chiral IL present in the NMR solu-
tion.13a We studied the concentration effect of CIL 14 on
the chemical shift difference (indicated by the Dd values)
of two diastereomeric –CF3 groups as described in Figure
6. The results show that as the concentration of chiral IL
increased, the chemical shift differences (Dd values) also in-
crease. A significant increment of 6.1 Hz in the Dd value of

668
V. Kumar et al. / Tetrahedron: Asymmetry 19 (2008) 664–671
4.1. Procedure for tosylation of D-isomannide
mide (TBAB) (2 g) were added, followed by the addition
of ethyl bromide (29.11 mL, 0.39 mol). The reaction mix-
ture was then stirred at room temperature and the progress
of the reaction was monitored on TLC using 30% ethyl ace-
tate/hexanes as solvent system. After completion of the
reaction in around 24 h, some more water was added to
the reaction mixture (50 mL). The organic layer was sepa-
rated and the aqueous layer was washed further with
dichloromethane (2 ꢂ 50 mL). The combined organic lay-
ers were dried over anhydrous Na2SO4 and then concen-
trated under vacuum. The crude product was purified
further by silica gel column chromatography using ethyl
acetate/hexanes as a solvent system in increasing order of
D-Isomannide 1 (50 g, 0.34 mol) was dissolved in dichloro-
methane (150 mL) in a round bottom flask followed by the
addition of pyridine (55 mL). The reaction mixture was
stirred in an ice-bath at 0–5 °C, followed by slow addition
of p-toluenesulfonyl chloride (98 g, 0.51 mol). After the
addition of p-toluenesulfonyl chloride, the reaction mixture
was stirred at room temperature for 12 h. The reaction
mixture was then diluted with some more dichloromethane
(50 mL) and then washed with 1 M HCl (2 ꢂ 100 mL),
water (100 mL), and brine (100 mL). The organic layer
was then dried over anhydrous Na2SO4 and concentrated
under vacuum. The crude product was a mixture of com-
pounds 9 and 10 which were separated and purified by sil-
ica gel column chromatography using chloroform/
methanol as solvent system in increasing order of polarity.
polarity to obtain compound 11 as a light yellow oil in
22
85% yield (36.24 g) from compound 2. ½aꢃD ¼ þ91:4 (c
1
0.85, MeOH); H NMR (300 MHz, CDCl3): d 1.21 (3H,
t, J = 7.0 Hz, CH3CH2O), 2.44 (3H, s, CH3), 3.45–3.70
(3H, m, H3b and CH3CH2O), 3.80 (1H, dd, J(H7a,
H7b) = 9.4 Hz and J(H7a,H8) = 7.2 Hz, H7b), 3.90–4.02
(3H, m, H3a, H7a and H4), 4.47 (1H, t, J(H1,H5) =
J(H4,H5) = 4.5 Hz, H5), 4.52 (1H, t, J(H1,H5) =
J(H1,H8) = 4.5 Hz, H1), 4.84–4.91 (1H, m, H8), 7.33 (2H,
4.1.1. (1S,4R,5R,8R)-8-(p-Toluenesulfonyloxy)-2,6-dioxabi-
cyclo [3.3.0] octan-4-ol 9. This compound was obtained as
a white solid, melting point 100–102 °C (lit. mp 102–
22
104 °C)22a in 44% (45 g) yield. ½aꢃD ¼ þ95:3 (c 1, MeOH);
1H NMR (300 MHz, CDCl3): d 2.45 (3H, s, CH3), 2.59
(1H, br s, OH), 3.54 (1H, dd, J(H3a,H3b) = 9.2 Hz and
J(H3b,H4) = 7.2 Hz, H3b), 3.78 (1H, dd, J(H7a,
H7b) = 9.4 Hz and J(H7b,H8) = 7.5 Hz, H7b), 3.93–4.04
(2H, m, H3a and H7a), 4.28 (1H, q, J = 6.3 Hz, H4), 4.43
(1H, t, J(H1,H5) = J(H4,H5) = 4.9 Hz, H5), 4.49 (1H, t,
J(H1,H5) = J(H1,H8) = 4.9 Hz, H1), 4.87–4.93 (1H, m,
d, J = 8.3 Hz, H3 and H5 ), 7.81 (2H, J = 8.3 Hz, H2 and
0
0
0
H6 ). 13C NMR (75.5 MHz, CDCl3): d 15.68 (CH3CH2O),
0
22.03 (CH3), 66.68 (CH3CH2O), 70.68 (C-3), 71.25 (C-7),
79.10 (C-4), 80.26 (C-5), 80.59(C-1), 80.63 (C-8), 128.33
(C-30 and C-50), 130.25 (C-20 and C-60), 133.70 (C-40) and
145.51 (C-10); HRMS (ESI): m/z 351.0862 ([M+Na]+,
C15H20O6SNa calcd, 351.0878).
0
0
H8), 7.36 (2H, d, J = 8.4 Hz, H3 and H5 ), 7.83 (2H,
J = 8.4 Hz, H2 and H6 ); 13C NMR (75.5 MHz, CDCl3):
d 20.51 (CH3), 68.89 (C-3), 71.17 (C-4), 72.77 (C-7),
77.31 (C-5), 78.89 (C-1), 80.28 (C-8), 126.83 (C-30 and
C-50), 128.77 (C-20 and C-60), 131.91 (C-40), 144.13 (C-10);
HRMS (ESI) m/z 323.0553 ([M+Na]+, C13H16O6SNa
calcd, 323.0565).
0
0
4.3. (1R,4R,5R,8S)-4-Ethoxy-8-(benzylamino)-2,6-dioxabi-
cyclo [3.3.0] octane 12
To compound 11 (27 g, 82.07 mmol) taken in a round bot-
tom flask, benzylamine (80 mL) was added and the reac-
tion mixture stirred at 180 °C under
a
nitrogen
4.1.2.
(1S,4R,5S,8R)-4,8-Bis(p-toluenesulfonyloxy)-2,6-
atmosphere for 12 h. After consumption of the starting
material (on TLC), the reaction mixture was cooled to
room temperature and excessive benzylamine was removed
under reduced pressure and the residue dissolved in dichlo-
romethane (150 mL). The white crystalline solid of tosyl-
benzylamine salt was filtered off and the filtrate was washed
with water and then dried over anhydrous Na2SO4 and
concentrated under vacuum. The crude product still con-
taining a slight amount of benzylamine and some complex
mixture of non-polar impurities was purified by silica gel
chromatography using 50% ethyl acetate/hexanes as sol-
vent system in increasing order of polarity. The purified
dioxabicyclo [3.3.0] octane 10. This compound was ob-
tained as a white solid with melting point 82–84 °C (lit.
22
mp 89–90 °C)29 in 28% (44 g) yield. ½aꢃD ¼ þ78:5 (c 0.6,
MeOH); 1H NMR (300 MHz, CDCl3): d 2.45 (6H, s,
2 ꢂ CH3), 3.72 (2H, dd, J(H7a,H7b) = J(H3a,H3b) = 9.4 Hz,
J(H7b,H8) = J(H3b,H4) = 7.6 Hz, H3b and H7b), 3.90 (2H,
dd,
J(H7a,H7b) = J(H3a,H3b) = 9.4 Hz,
J(H7a,H8) =
J(H3a,H4) = 6.6 Hz, H3a and H7a), 4.45–4.47 (2H, m,
J(H1,H5) = J(H1,H8) = J(H4,H5) = 4.0 Hz, H1 and H5),
4.80–4.87 (2H, m, H4 and H8), 7.34 (4H, d, J = 8.1 Hz,
0
00
0
00
0
H3 , H3 , H5 and H5 ) and 7.80 (4H, d, J = 8.1 Hz, H2 ,
H2 , H6 and H6 ); 13C NMR (75.5 MHz, CDCl3): d 20.49
(2 ꢂ CH3), 68.91 (C-3 and C-7), 76.84 (C-1 and C-5),
78.80 (C-4 and C-8), 126.75 (C-30, C300, C-50, and C-500),
128.80 (C-20, C200, C-60, and C-600), 131.81 (C-40 and C-400)
and 144.19 (C-10 and C-100); HRMS (ESI): m/z 477.0659
([M+Na]+, C20H22O8S2Na calcd, 477.0654).
compound 12 was obtained as a light yellow oil in 60%
00
0
00
22
(13 g). ½aꢃD ¼ þ94:0 (c 1.076, MeOH); 1H NMR
(300 MHz, CDCl3): d 1.25 (3H, t, J = 6.9 Hz, CH3CH2O),
1.56 (1H, br s, NH), 3.34–3.36 (1H, m, H8), 3.48–3.81 (6H,
m, CH3CH2O, NHCH2Ph, H3a and H3b), 3.90–3.99 (2H,
m, H4 and H7b), 4.05 (1H, dd, J(H7a,H7b) = 9.3 Hz and
J(H7a,H8) = 5.0 Hz, H7a), 4.45 (1H, br d, J(H1,H5) =
4.3 Hz, H1), 4.60 (1H, t, J(H1,H5) = J(H4,H5) = 4.3 Hz,
H5), 7.23–7.35 (5H, m, aromatic H’s); 13C NMR
(75.5 MHz, CDCl3): d 15.74 (CH3CH2O), 52.49 (NHCH2-
Ph), 65.44 (C-8), 66.49 (CH3CH2O), 70.17 (C-3), 74.56
(C-7), 80.51 (C-4), 80.55 (C-1), 88.15 (C-5), 127.55 (C-40),
128.52 (C-30 and C-50), 128.87 (C-20 and C-60), and 140.08
4.2. (1S,4R,5R,8R)-4-Ethoxy-8-(p-toluenesulfonyloxy)-2,6-
dioxabicyclo [3.3.0] octane 11
Isomannide monotosylate 9 (39 g, 0.13 mol) was dissolved
in dichloromethane (250 mL) in a round bottom flask, 50%
aq KOH solution (30 mL) and tetrabutylammonium bro-

V. Kumar et al. / Tetrahedron: Asymmetry 19 (2008) 664–671
669
(C-10); HRMS (ESI): m/z 264.1587 ([M+H]+, C15H22NO3
calcd, 264.1600).
132.63 (C-10), 134.44 (C-20 and C-60); 19F NMR
(282.4 MHz, acetone-d6):
d
ꢀ80.27 ((CF3 SO2)2Nꢀ);
HRMS (ESI): m/z292.1899 ([M]+, C17H26NO (the organ-
þ
3
4.4. ((1R,4R,5R,8S)-4-Ethoxy-2,6-dioxabicyclo [3.3.0]
octan-8-yl)-dimethylbenzylammonium iodide 13
ic cationic moiety) calcd, 292.1913).
4.6. ((1R,4R,5R,8S)-4-Ethoxy-2,6-dioxabicyclo [3.3.0]
octan-8-yl)-dimethylbenzylammonium hexafluorophosphate
15
The sec-amine 12 (15 g, 57.03 mmol) was dissolved in ace-
tonitrile (150 mL) and anhydrous K3CO3 (1 equiv) was
added, followed by the addition of methyl iodide (21 mL,
0.34 mol). The reaction mixture was then stirred at room
temperature. After completion of the reaction (14 h), the
K2CO3 was filtered off and the filtrate was concentrated
under vacuum. The crude product was washed once with
To a solution of the iodide salt 13 (2 g, 4.8 mmol) in water
(15 mL) at 50 °C, KPF6 (1.1 g, 5.7 mmol) was added and
the reaction mixture was stirred for 6 h. The product sepa-
rated as a white solid, and then filtered, and washed twice
with water to remove any remaining starting material. The
acetone to give the desired compound 13 as a white solid,
22
mp = 170 °C in 83% (19.83 g) yield. ½aꢃD ¼ þ54:8 (c 0.96,
desired compound 15 was obtained in 81% (1.7 g) yield,
22
MeOH); 1H NMR (300 MHz, CDCl3): d 1.19 (3H, t,
J = 6.9 Hz, CH3CH2O), 3.34 (3H, s, NCH3), 3.46–3.71
(5H, m, NCH3 and CH3CH2O), 3.76 (1H, dd,
J(H3a,H3b) = 9.8 and J(H3a,H4) = 4.4 Hz, H3a), 3.84 (1H,
dd, J(H3a,H3b) = 9.8 Hz and J(H3b,H4) = 5.0 Hz, H3b),
3.93–3.95 (1H, m, H8), 4.02 (1H, q, J = 4.9 Hz, H4), 4.28
(1H, dd, J(H7a,H7b) = 12.0 Hz and J(H7a,H8) = 6.0 Hz,
H7a), (1H, dd, J(H7a,H7b) = 12.0 Hz and J(H7b,H8) = 2.0
Hz, H7b), 5.07 (1H, t, J(H1,H5) = J(H4,H5) = 5.7 Hz, H5),
5.15 (1H, d, J(Hx,Hy) = 13.0 Hz, Hx), 5.24 (1H, d,
J(Hx,Hy) = 13.0 Hz, Hy), 5.79 (1H, d, J(H1,H5) = 5.7 Hz,
mp = 95 °C. ½aꢃD ¼ þ49:8 (c 0.92, MeOH); 1H NMR
(300 MHz, CDCl3): d 1.17 (3H, t, J = 6.9 Hz, CH3CH2O),
2.98 (3H, s, NCH3), 3.07 (3H, s, NCH3), 3.44–3.68 (2H, m,
CH3CH2O), 3.72–3.82 (3H, m, H3a, H3b, and H8), 3.97
(1H, q, J = 4.9 Hz, H4), 4.23–4.36 (2H, m, H7a and H7b),
4.46 (1H, d, J(Hx,Hy) = 13.4 Hz, Hx), 4.56 (1H, d,
J(Hx,Hy) = 13.4 Hz, Hy), 4.84 (1H, t, J(H1,H5) =
J(H4,H5) = 5.4 Hz, H5), 5.09 (1H, d, J(H1,H5) = 5.4 Hz,
H1), 7.43–7.49 (5H, m, aromatic H’s); 13C NMR
(75.5 MHz, CDCl3): d 15.33 (CH3CH2O), 48.58 and
48.79 (2 ꢂ NCH3), 66.50 (CH2Ph), 67.51 (CH3CH2O),
68.61 (C-3), 71.51 (C-7), 77.23 (C-8), 78.79 (C-4), 81.19
(C-5), 82.43 (C-1), 125.92 (C-40), 129.52 (C-30 and C-50),
131.19 (C-10), 133.16 (C-20 and C-60); 19F NMR
(282.4 MHz, CD3CN): d ꢀ75.38 ðPF6ꢀÞ; HRMS (ESI):
0
0
0
H1), 7.40–7.47 (3H, m, H3 , H4 and H5 ) and 7.72–7.75
(2H, m, H2 and H6 ); 13C NMR (75.5 MHz, CDCl3): d
15.76 (CH3CH2O), 49.61 and 49.96 (2 ꢂ NCH3), 66.89
(CH2Ph), 67.80 (CH3CH2O), 68.67 (C-3), 72.23 (C-7),
78.00(C-8), 79.28 (C-4), 82.25 (C-5), 83.01 (C-1), 126.87
(C-40), 129.67 (C-30 and C-50), 131.29 (C-20 and C-60), and
0
0
m/z 292.1897 ([M]+, C17H26NO3 (the organic cationic
þ
moiety) calcd, 292.1913).
133.96 (C-10); HRMS (ESI): m/z 292.1894 ([M]+,
þ
C17H26NO3
292.1913).
(the organic cationic moiety) calcd,
4.7. ((1R,4R,5R,8S)-4-Ethoxy-2,6-dioxabicyclo [3.3.0]
octan-8-yl)-dimethylbenzylammonium trifluoroacetate 16
4.5. ((1R,4R,5R,8S)-4-Ethoxy-2,6-dioxabicyclo [3.3.0]
octan-8-yl)-dimethylbenzylammonium bis(triflic)imide 14
To a solution of the iodide salt 13 (2 g, 4.8 mmol) in water
(15 mL) at 50 °C, an aqueous solution of CF3COOAg
(1.06 g, 4.8 mmol in 3 mL water) was added. The yellow
precipitate of AgI started forming, the reaction mixture
was stirred for 30 min and the AgI precipitate was filtered
off. A fresh solution of 1 M CF3COOAg was added to the
filtrate dropwise until the precipitation was completed, the
last excessive drop of CF3COOAg solution was neutralized
by a drop of 1 M solution of iodide 13. The AgI precipitate
was again filtered off and the filtrate was concentrated un-
der vacuum to remove water. The compound 16 was thus
obtained as a colorless oil in 72.43% (1.4 g) yield.
½aꢃD ¼ þ53:1 (c 1, MeOH); H NMR (300 MHz, CDCl3):
d 1.17 (3H, t, J = 6.9 Hz, CH3CH2O), 3.05 (3H, s,
NCH3), 3.13 (3H, s, NCH3), 3.44–3.69 (2H, m,
CH3CH2O), 3.76 (2H, ddd, J(H3a,H3b) = 9.6 Hz,
J(H3a,H4) = 4.9 Hz and J(H3b,H4) = 5.1 Hz, H3a and
H3b), 3.85–3.91 (1H, m, H8), 3.97 (1H, q, J = 5.2 Hz,
To the iodide salt 13 (2 g, 4.8 mmol) in water (15 mL) in a
RB flask at 60 °C (high temperature was needed because
iodide salt 13 was not completely soluble in water at room
temperature), lithium bis(triflic) amide (1.6 g, 5.7 mmol)
was added and the reaction mixture was stirred for 6 h,
after which the product separated as a highly viscous oil
at the bottom of a round bottom flask. The water was dec-
anted off and the residue was further washed with water
(3 ꢂ 10 mL) when the desired compound 14 was obtained
22
22
1
as a viscous oil in 85% (2.3 g) yield. ½aꢃD ¼ þ35:6 (c 0.88,
MeOH); 1H NMR (300 MHz, CDCl3): d 1.20 (3H, t,
J = 6.9 Hz, CH3CH2O), 3.00 (3H, s, NCH3), 3.07 (3H, s,
NCH3), 3.48–3.73 (2H, m, CH3CH2O), 3.76–3.86 (3H, m,
H3a, H3b and H8), 4.01 (1H, q, J = 5.1 Hz, H4), 4.27–4.37
(2H, m, H7a and H7b), 4.48 (1H, d, J(Hx,Hy) = 13.2 Hz,
Hx), 4.57 (1H, d, J(Hx,Hy) = 13.2 Hz, Hy), 4.87 (1H, t,
J(H1,H5) = J(H4,H5) = 5.7 Hz, H5), 5.12 (1H, d,
J(H1,H5) = 5.7 Hz, H1), 7.44–7.54 (5H, m, aromatic H’s);
13C NMR (75.5 MHz, CDCl3): d 16.59 (CH3CH2O),
49.93 and 50.35 (2 ꢂ NCH3), 67.86 (CH2Ph), 68.90
(CH3CH2O), 70.02 (C-3), 72.98 (C-7), 79.17(C-8), 80.07
(C-4), 82.57 (C-5), 83.81 (C-1), 121.08 (q, J = 321.2,
(CF3SO2)2N), 126.98 (C-40), 130.87 (C-30 and C-50),
H4),
4.26
(1H,
dd,
J(H7a,H7b) = 11.9 Hz
and
J(H7a,H8) = 6.1 Hz, H7a), 4.41 (1H, dd, J(H7a,
H7b) = 11.9 Hz and J(H7b,H8) = 3.0 Hz, H7b), 4.61 (1H,
d, J(Hx,Hy) = 13.0 Hz, Hx), 4.69 (1H, d, J(Hx,Hy) =
13.0 Hz, Hy), 4.87 (1H, t, J(H1,H5) = J(H4,H5) = 5.5 Hz,
H5), 5.29 (1H, d, J(H1,H5) = 5.5 Hz, H1), 7.34–7.56 (5H,
m, aromatic H’s); 13C NMR (75.5 MHz, CDCl3): d 16.32
(CH3CH2O), 49.48 and 49.79 (2 ꢂ NCH3), 67.51 (CH2Ph),

670
V. Kumar et al. / Tetrahedron: Asymmetry 19 (2008) 664–671
68.77 (CH3CH2O), 68.84 (C-3), 74.46 (C-7), 78.45 (C-8),
79.97 (C-4), 82.48 (C-5), 83.50 (C-1), 118.36 (q,
J = 296.5, CF3), 127.73 (C-40), 130.30 (C-30 and C-50),
131.81 (C-10), 134.39 (C-20 and C-60), and 162.10 (d,
J = 32.95 Hz, COOꢀ); 19F NMR (282.4 MHz, CDCl3): d
sumption of mono-ammonium iodide 13. The last excess
drop of CF3SO3Ag solution was neutralized by adding a
drop of 1 M aqueous mono-ammonium iodide 13 solution.
The AgI precipitate was filtered off and the compound 18
was obtained by removing water under vacuum as a white
22
ꢀ79.75 (CF3COOꢀ); HRMS (ESI): m/z 292.1897 ([M]+,
solid in 76.2% (1.6 g) yield, mp = 80 °C. ½aꢃD ¼ þ60:5 (c 1,
C17H26NO3
292.1913).
(the organic cationic moiety) calcd,
MeOH); 1H NMR (300 MHz, CDCl3): d 1.18 (3H, t,
J = 6.9 Hz, CH3CH2O), 3.07 (3H, s, NCH3), 3.15 (3H, s,
NCH3), 3.40–3.67 (2H, m, CH3CH2O), 3.71–3.85 (3H, m,
H3a,H3b and H8), 3.98 (1H, q, J = 4.9 Hz, H4), 4.26 (1H,
dd, J(H7a,H7b) = 12.0 Hz and J(H7a,H8) = 5.9 Hz, H7a),
4.40 (1H, dd, J(H7a,H7b) = 12.0 Hz and J(H7b,H8) =
2.4 Hz, H7b), 4.63 (1H, d, J(Hx,Hy) = 13.1 Hz, Hx), 4.72
(1H, d, J(Hx,Hy) = 13.1 Hz, Hy), 4.89 (1H, t, J(H1,H5) =
J(H4,H5) = 5.4 Hz, H5), 5.30 (1H, d, J(H1,H5) = 5.4 Hz,
H1), 7.42–7.56 (5H, m, aromatic H’s); 13C NMR
(75.5 MHz, CDCl3): d 16.33 (CH3CH2O), 49.48 and
49.79 (2 ꢂ NCH3), 67.48 (CH2Ph), 68.74 (CH3CH2O),
69.03 (C-3), 72.44 (C-7), 78.71 (C-8), 79.90 (C-4), 82.39
(C-5), 83.44 (C-1), 121.66 (q, J = 320.1, CF3), 127.32
(C-40), 130.39 (C-30 and C-50), 132.13 (C-10), 134.32
(C-20 and C-60); 19F NMR (282.4 MHz, CDCl3): d
þ
4.8. ((1R,4R,5R,8S)-4-Ethoxy-2,6-dioxabicyclo [3.3.0]
octan-8-yl)-dimethylbenzylammonium tetrafluoroborate 17
Tetrafluoroboric acid (purchased as a 48% solution in
water) (5.76 mmol, 1.1 mL) was mixed with an aqueous
suspension of silver oxide (667 mg, 2.88 mmol) in a conical
flask covered with aluminum foil (silver oxide is light sen-
sitive). The mixture was stirred until the solution became
clear. The aqueous solution of silver tetrafluoroborate thus
formed was mixed with the aqueous solution of mono-
ammonium iodide 13 (2 g, 4.8 mmol) at 60 °C and the reac-
tion mixture was stirred for 30 min. The silver iodide
precipitate was filtered off and 1 M AgBF4 solution was
added to the filtrate dropwise to ensure total consumption
of mono-ammonium iodide 6. The last excess drop of
AgBF4 solution was neutralized by adding a drop of 1 M
aqueous mono-ammonium iodide 13 solution. Finally,
the AgI precipitate was filtered off and compound 17 crys-
tallized out from the filtrate on cooling in ice bath as a
ꢀ79.21 ðCF 3SO3ꢀÞ; HRMS (ESI): m/z 292.1900 ([M]+,
þ
C17H26NO3
292.1913).
(the organic cationic moiety) calcd,
4.10. 19F NMR experiments
white solid in 72.22% (1.3 g) yield, mp = 150 °C.
The racemic Mosher’s silver salt (0.076 mmol, 26 mg) was
mixed with a solution of CIL 13 (0.076 mmol, 32 mg) in
1 mL CD3CN to exchange their anions at room tempera-
ture. The AgI precipitate thus formed was filtered off and
the filtrate containing racemic Mosher’s acid chiral ammo-
nium salt A was transferred to NMR tube and subjected to
19F NMR spectral recording without isolation. The same
solution was mixed with CILs 13–18 (3.5 equiv) and again
analyzed by 19F NMR spectroscopy.
22
½aꢃD ¼ þ61:3 (c 1, MeOH); 1H NMR (300 MHz, CD3CN):
d 1.17 (3H, t, J = 7.0 Hz, CH3CH2O), 2.93 (3H, s, NCH3),
2.98 (3H, s, NCH3), 3.49–3.74 (3H, m, H3b and
CH3CH2O), 3.84 (1H, dd, J(H3a,H3b) = 9.5 Hz,
J(H3a,H4) = 5.3 Hz, H3a), 3.92–3.96 (1H, m, H8), 4.02
(1H, q, J = 5.3 Hz, H4), 4.24 (1H, dd, J(H7a,H7b) =
11.9 Hz and J(H7a,H8) = 5.4 Hz, H7a), 4.37 (1H,
dd, J(H7a,H7b) = 11.9 Hz and J(H7b,H8) = 4.2 Hz, H7b),
4.48 (2H, s, CH2Ph), 4.82 (1H, t, J(H1,H5) =
J(H4,H5) = 5.3 Hz, H5), 5.11 (1H, d, J(H1,H5) = 5.3 Hz,
H1), 7.49–7.60 (5H, m, aromatic H’s); 13C NMR
(75.5 MHz, CD3CN): d 15.79 (CH3CH2O), 49.45 and
49.59 (2 ꢂ NCH 3), 66.97 (CH2Ph), 68.53 (CH3CH2O),
68.59 (C-3), 72.10 (C-7), 79.73 (C-8), 79.77 (C-4), 82.39
(C-5), 83.11 (C-1), 127.75 (C-10), 130.29 (C-30 and C-50),
131.96 (C-40), 134.39 (C-20 and C-60); 19F NMR
(282.4 MHz, CD3CN): d ꢀ151.08 (BF4ꢀ); HRMS (ESI):
4.10.1. Effect of IL concentration. In different sets of
experiments, the CD3CN solution of Mosher’s acid chiral
ammonium salt A was mixed with different amounts of
CIL 14 (2 equiv, 3.5 equiv, 7 equiv, and 10 equiv) and the
effect of concentration of CIL was probed by 19F NMR
spectroscopy.
m/z 292.1905 ([M]+, C17H26NO
(the organic cationic
þ
3
Acknowledgments
moiety) calcd, 292.1913).
This work was supported by a US Department of Energy
Laboratory Directed Research and Development Program
at Brookhaven National Laboratory. The authors would
like to thank EMD Chemicals Inc., for the generous gift
of chemicals for chromatography.
4.9. ((1R,4R,5R,8S)-4-Ethoxy-2,6-dioxabicyclo [3.3.0]
octan-8-yl)-dimethylbenzylammonium trifluorosulfonate 18
Trifluoromethanesulfonic acid (0.52 mL, 5.8 mmol) was
mixed with an aqueous suspension of silver oxide
(667 mg, 2.88 mmol) in a conical flask covered with alumi-
num foil. The mixture was stirred until the solution became
clear. The aqueous solution of silver trifluoromethanesulfo-
nate thus formed was mixed with the aqueous solution of
mono-ammonium iodide 13 (2 g, 4.8 mmol) at 60 °C and
the reaction mixture was stirred for 30 min. The silver
iodide precipitate was filtered off and 1 M CF3SO3Ag solu-
tion was added to the filtrate dropwise to ensure total con-
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