New chiral zwitterionic phosphorus heterocycles: Synthesis, structure, properties and application as chiral solvating agents

Article abstract of DOI:10.1002/chem.201300062

A family of new chiral zwitterionic phosphorus-containing heterocycles (zPHC) have been derived from methylene-bridged bis(imidazolines). These structures were unambiguously determined, including single-crystal XRD analysis for two compounds. The stability, acid/base and electronic properties of these dipolar phosphorus heterocycles were subsequently investigated. zPHCs can be successfully employed as a new class of chiral solvating agents for the enantiodifferentiation of chiral carboxylic and sulfonic acids by NMR spectroscopy. The stoichiometry and binding constants for the donor-acceptor complexes formed were established by NMR titration methods. A convenient synthetic approach to a new class of chiral zwitterionic phosphorus-containing heterocycles starting from methylene-bridged bis(imidazolines) was designed and executed. Stability and properties of the synthesized compounds were investigated. The applicability of the designed compounds as chiral solvating agents for the determination of the enantiomeric excesses of chiral acids was demonstrated. Copyright

Full text of DOI:10.1002/chem.201300062

FULL PAPER
DOI: 10.1002/chem.201300062
New Chiral Zwitterionic Phosphorus Heterocycles: Synthesis, Structure,
Properties and Application as Chiral Solvating Agents
Andrey E. Sheshenev,[a] Ekaterina V. Boltukhina,[a] Anastasiya A. Grishina,[b]
Ivana Cisarˇova,[c] Ilya M. Lyapkalo,[b] and King Kuok (Mimi) Hii*[a]
In memory of Ilya M. Lyapkalo
Abstract: A family of new chiral zwitterionic phosphorus-containing heterocycles
(zPHC) have been derived from methylene-bridged bis(imidazolines). These struc-
tures were unambiguously determined, including single-crystal XRD analysis for
two compounds. The stability, acid/base and electronic properties of these dipolar
Keywords: binding constants · chir-
ality
· enantioselectivity · NMR
phosphorus heterocycles were subsequently investigated. zPHCs can be successful-
ly employed as a new class of chiral solvating agents for the enantiodifferentiation
of chiral carboxylic and sulfonic acids by NMR spectroscopy. The stoichiometry
and binding constants for the donor–acceptor complexes formed were established
by NMR titration methods.
spectroscopy · phosphorus hetero-
cycles · zwitterions
Introduction
ticular enantiomer can also be established by further NMR
experiments.[4]
Significant advances in asymmetric chemistry have expedit-
ed demand for faster methods of analysis for enantiomeric
mixtures.[1,2] Although chiral chromatography (LC or GC) is
the accepted industrial standard for quantifying enantiomer-
ic purity, these methods typically require several minutes, if
not hours, and the assignment of the absolute stereochemis-
try can only be achieved by correlation with known com-
pounds. In contrast, the use of a chiral derivatising agent
(CDA) or chiral solvating agent (CSA) allows the enantio-
meric ratio to be determined in a few minutes by NMR
spectroscopy,[3] which is an available, automated and high-
throughput technique available in modern laboratories. As
an added advantage, the absolute stereochemistry of a par-
CSAs form diastereomeric complexes with chiral analytes
through weak intermolecular interactions, which lead to
chemical-shift inequivalence in analogous nuclei. Because
the technique is non-destructive, they are inherently more
desirable than CDAs, which require the formation of a cova-
lent bond. In general, there are two main types of interac-
tions between a CSA and the analyte: 1) Host–guest interac-
tions that involve the intercalation of the enantiomer within
a supramolecular architecture, such as cyclodextrins, crown
ethers, or peptides; and/or 2) Donor–acceptor interactions,
mostly through H bonding with certain functional groups,
for example, amines, alcohols, acids and sulfoxides.
To date, there has only been one report of zwitterionic
CSAs, comprising of a chiral imidazolinium moiety with a
sulfonate or sulfamate counteranion (Figure 1).[5] These mol-
ecules could provide multiple points of ionic contact for
greater chiral recognition. However, because the charges are
well separated, this can limit their solubility in organic sol-
vents, for example, the best-performing compound III (R1 =
Ph, R2 =2-MeC6H4) is not soluble in toluene.
[a] Dr. A. E. Sheshenev, Dr. E. V. Boltukhina, Dr. K. K. Hii
Department of Chemistry, Imperial College London
Exhibition Road, SW7 2AZ London (UK)
Fax : (+44)2075945804
E-mail: mimi.hii@imperial.ac.uk
[b] A. A. Grishina, Dr. I. M. Lyapkalo
Institute of Organic Chemistry and Biochemistry AS CR, v.v.i.
Flemingovo nam. 2, 166 10 Prague 6 (Czech Republic)
ˇ
[c] Dr. I. Cisarova
Department of Inorganic Chemistry, Charles University
Hlavova 2030, 12840 Prague 2 (Czech Republic)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201300062. It includes data for
new compounds, experimental procedures, crystallographic details,
1
copies of H and 13C NMR spectra. X-ray crystallographic structures
are provided as .cif files, as well as the checkpoint file for the calculat-
ed structure of compound 4a.
Figure 1. Chiral zwitterionic imidazolinium sulfonates/sulfamates.
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Herein, we disclose the preparation, characterisation and
properties of a structurally new class of chiral zwitterionic
phosphorus heterocycles and their potential applications as
CSAs for enantiodiscrimination of chiral carboxylic and sul-
fonic acids.
properties can be achieved by modifying N-substituents of
the parent MBI.
Improved synthesis of MBIs: MBI compounds 3 were pre-
pared from the commercially available N-Boc protected
amino acids, N-Boc-S-valine (5a), N-Boc-S-phenylalanine
(5b) and N-Boc-R-phenylglycine (5c), by modifying a four-
step procedure previously described by Pfaltz and co-work-
ers (Scheme 1).[15] The N-Boc moiety in 6 was first un-
Results and Discussion
Design of zwitterionic phosphorus heterocycles: Prior to this
work, examples of zwitterionic phosphorus compounds, con-
À
taining a PO2 fragment with a positively charged sp2 nitro-
gen atom, are limited to pyridi-
nium or imidazolium adducts of
metaphosphates (Figure 2).[6–8]
These were reported as stable,
crystalline compounds that can
be isolated and fully character-
ised.
Figure 2. Known zwitterionic
PV compounds.
Chiral C2-symmetric bisoxazolines 1 (BOX, Figure 3) are
a unique class of privileged ligands for many metal-catalysed
asymmetric reactions.[9–13] Of these, the class of zwitterionic
boron-BOXates 2 were derived in 2006 by Bandini et al.,
and were shown to be moderately successful catalysts for
the asymmetric reduction of prochiral ketones.[14]
Scheme 1. Synthesis of MBI scaffolds 3. a) NMM, ClCO2iBu, R’NH2;
b) AcCl/MeOH, 08C to RT, 24 h; c) LiAlH4, THF, reflux, 24–48 h;
d) CH2(CACHTUNGRTNEUNG(=NH)OEt)2·2HCl (8), CH2Cl2, RT to reflux, 24–96 h;
e) NaOH/CH2Cl2/H2O.
masked by using AcCl/MeOH. The resultant hydrochloride
salts were then directly employed in a reduction step with
LiAlH4, leading to an improved yield of 1,2-diamines 7. Sub-
sequently, the transformation of 7 into the desired MBIs 3
was achieved in two steps: the condensation of diamines 7
with diethyl malonimidate dihydrochloride 8 gave MBI de-
rivatives 9 as HCl salts, isolated in good-to-excellent yields
as easy-to-handle crystalline compounds. From these, the
corresponding free MBI bases 3 can be released quantita-
tively, by treatment with 10% aqueous NaOH, immediately
before their deployment in the subsequent reactions.
Figure 3. Zwitterionic structures derived from BOX (1) and MBI (3).
Compound 9 f was transformed into its tetrafluoroborate
salt by ion exchange with aqueous NaBF4 (3m) to give
single crystals suitable for X-ray crystallographic analysis
(Figure 5). The molecular structure of (S,S)-3 f·HBF4 is
largely similar to its unsubstituted analogue of 2,2’-methyl-
In 2007, methylene-bridged bis(imidazoline) ligands 3
(MBI) were reported as more flexible analogues of
BOX.[15,16] Herein, the MBI scaffold was employed as a
means of providing a rigid, chiral framework to construct
zwitterionic PV heterocycles 4, which we abbreviated herein
as zPHC (Figure 3).
ene-bis(4,5-dihydro-1H-imidazole)
hydrochloride
(H-
MBI).[16] The only significant difference was the dihedral
angle, t, between least-square planes of two five-membered
rings, being 20.09(8)8 for the 3 f·HBF4, compared to
15.69(9)8 for H-MBI. However, this angle is rather flexible
À
By embedding a negatively charged PO2 fragment within
a bisamidinium six-membered ring chelate, the resultant
product may be stabilised by resonance structures IV and V
(Figure 4); further, fine tuning of the steric and electronic
À
and can be strongly affected by N H···X hydrogen bonds.
Free MBI bases 3 exist as either one of two possible tau-
tomeric forms in solution, which are strongly dependent
upon the solvent. This was demonstrated by recording a
1
series of H NMR spectra of 3 f in seven different solvents
at 238C (Table 1). In all cases, the conjugated tautomer (A)
was thermodynamically more favourable than the unconju-
gated tautomer (B). The greatest stabilisation was provided
by polar aprotic media, such as [D6]DMSO and [D6]acetone,
Figure 4. Resonance structures of 4.
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New Chiral Zwitterionic Phosphorus Heterocycles
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Table 1. Solvent-dependent tautomerisation of 3 f at 238C.
action proceeded smoothly to give the target
zPHCs 4a–j within 24 h. Monitoring the progress of
the reaction by 31P NMR spectroscopy, the forma-
tion of the ionic intermediate 10 can be detected in
the crude reaction mixture, indicated by a distinct
singlet resonance between À1 to À3 ppm. Upon
treatment with a basic solution, the hydrolysis of 10
to the inner salt 4 was denoted by an upfield shift
to between À13 to À15 ppm.
Solvent
N
ACHTUNGTRENNUNG
A/B[a]
1
[a] Determined by comparison of H NMR spectra integrals of N-CH3 or BnCHN sig-
The method was applied to the synthesis of a
family of ten zPHCs (4a–j), which were isolated in
good-to-excellent yields (74–94%). The zwitterionic
products were fully characterised (see the Support-
nals.
ing Information), and further confirmation was provided by
single-crystal X-ray analysis of compounds 4a and 4 f (Fig-
ures 6 and 7). Both molecules have two-fold symmetry, with
the C2 axis dissecting the central methine carbon and phos-
phorus atom. It is interesting to note that the central six-
membered rings are not quite planar. Comparing the struc-
ture of these zPHC molecules with the parent MBI
(Figure 5), the incorporation of PO2 moiety does not appear
Figure 5. ORTEP representation of the molecular structure of (S,S)-
3 f·HBF4. The displacement parameters are drawn at 50% probability
À
level. The selected bond lengths [ꢁ] and angles [8]: N1 C2 1.3607(17),
À
À
À
À
N1 C5 1.4797(17), C2 N3 1.3348(17), N3 C4 1.4617(17), C4 C5
À
À
À
À
1.537(2), C2 C6 1.4012(18), C6 C8 1.3928(19), N7 C8 1.3562(18), C8
N9 1.3450(16), N9 C10 1.4562(19), N7 C11 1.4754(17), C10 C11
1.522(2); C8-C6-C2 125.97(12). Hydrogen-bond parameters for N1
À
À
À
À
À
H1···F1/N1···F1 2.9537(14) ꢁ, angle at H1 1518; for N7 H7···F3: N7···F3
2.9309(14) ꢁ, angle at H7 1458.
in which ratios of 13:1 and 14:1 were observed, correspond-
ing to a relative stabilisation energy of approximately
6.5 kJmolÀ1. On the other hand, the lowest ratio of 3:2 was
observed in CDCl3 (ca. 1 kJmolÀ1).
Figure 6. ORTEP representation of the molecular structure of (S,S)-4a.
The displacement parameters are drawn at 50% probability level. The
À
À
selected bond lengths [ꢁ] and angles [8]: P1 O1 1.4761(14), P1 N1
À
À
À
À
1.7116(16), N1 C2 1.359(2), N1 C5 1.492(2), C2 N3 1.345(2), N3 C4
Synthesis of zPHCs: The phosphorus heterocycle was
formed by the reaction between MBI and phosphorus oxy-
chloride (POCl3), performed at room temperature in dry
CH2Cl2 or THF, in the presence of NEt3 (Scheme 2). The re-
i
À
À
1.453(3), C4 C5 1.536(3), C2 C6 1.387(2); C2-C6-C2 118.8(2). Symmetry
codes: i) Àx+2, Ày, z.
Figure 7. ORTEP representation of the molecular structure of (S,S)-4 f.
The displacement parameters are drawn at 50% probability level. The
À
À
selected bond lengths [ꢁ] and angles [8]: P1 O1 1.4737(19), P1 N1
À
À
À
À
1.711(2), N1 C2 1.359(3), N1 C5 1.483(3), C2 N3 1.347(3), N3 C4
i
À
À
Scheme 2. Synthesis of zPHC 4. a) POCl3, NEt3, CH2Cl2, 08C to RT, 24 h;
b) aqueous NaOH (10%), RT.
1.454(3), C4 C5 1.536(4), C2 C6 1.391(3); C2-C6-C2 118.6(3). Symmetry
codes: i) Àx+2, Ày+2, z.
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K. K. Hii et al.
Table 2. Stability of compounds 4a, f, h (R’=Me) in neutral and basic
to affect the conjugation within imidazolines rings, because
the bond lengths found in 4a and 4 f are almost identical
with respective lengths of (S,S)-3 f·HBF4, with the exception
of a more acute angle at the central methine carbon, being
118.8 and 118.68 for 4a and 4 f, respectively, compared to
125.68 in 3 f.
The electronic properties of the zPHC compounds were
investigated by performing DFT calculation of the distribu-
tion of charges in 4a, which showed that the molecule pos-
sesses a sizeable dipole moment of 12D along the C2 axis
(Figure 8). Interestingly, although the negative charge is lo-
calised on the oxygen atoms, the positive charge is distribut-
ed extensively over the MBI framework.
solutions of [D6]DMSO/H2O (10:1 v/v).[a]
zPHC
pH
t [h]
T [8C]
Decomposition [%]
[c]
4a, f, h
neutral
24
1
24
24
1
24
24
1
RT
100
100
RT
100
100
RT
100
100
–
–
–
–
–
–
[c]
[c]
[c]
4a, f
basic[b]
basic[b]
[c]
[c]
4h
5
15
50
24
[a] Monitored by 1H NMR spectroscopy. The amount of decomposition
was measured by integrating the Me (R’) signal against an internal stand-
ard (anisole). [b] [D6]DMSO/H2O/50% aqueous KOH (10:1:1, v/v/v).
[c] No decomposition was observed within the detection limit.
À
À
The inherent nucleophilicity of the P O bond was exam-
ined by the reaction of 4a with a number of alkylating
agents: BnBr, MeI, TBSOTf and MeOTf. The formation of
the phosphoric acid ester 11 was only successful by using
MeOTf, showing the molecule to be weakly nucleophilic
(Scheme 3). Conversely, compound 11 is prone to hydrolysis,
reverting to the zPHC 4a upon exposure to aqueous NaOH
or KOH (10%) under ambient conditions. Thus, the cation–
anion interaction between the ion pair of 11 is weaker than
that found in the inner salt 4a.
Scheme 3. Methylation of zPHC 4a.
Figure 8. Electrostatic potential map of compound 4a, as was determined
by DFT calculations. Negative, neutral and positive potentials are repre-
sented in red, green and blue, respectively.
Applications of zPHC 4 as CSAs: Chiral carboxylic acids
can be found in many biologically active natural products, in
which they constitute a class of important chiral building
blocks in the development of agrochemical and pharmaceut-
ical products. For chiral HPLC and GC to be deployed for
enantiomeric excess (ee, %) determination, the presence of
a CO2H moiety in the analyte often requires derivatization
into the ester or amide to alter its polarity and/or volatility
for analysis. This can be potentially problematic, particularly
if the carboxylic acid has an intrinsically low reactivity due
to steric or electronic effects, as incomplete derivatization
can lead to errors in analysis. Consequently, the develop-
ment of CSAs for the analysis of chiral carboxylic acids is a
highly topical research area. Commercially available chiral
Properties of the phosphorus heterocycles 4: The zPHC
compounds 4 are stable as solids, which can be kept at ambi-
ent temperature for at least a year without decomposition.
They are soluble in common organic solvents and, in the
case of R’=Me, in water. The stability of three zPHC com-
pounds 4a, 4 f and 4h was also evaluated under neutral or
basic conditions in DMSO, at ambient and elevated temper-
atures (Table 2). All three compounds were hydrolytically
stable in a mixture of H2O/DMSO at neutral pH up to
1008C. However, upon addition of a hydroxide base, slow
decomposition of the phenyl-substituted zPHC 4h was de-
tected at room temperature, which was accelerated at 1008C
to form an intractable mixture of compounds. In contrast,
zPHC analogues 4a and 4 f, containing isopropyl and benzyl
substituents, respectively, were stable in the alkaline media
at 1008C for up to 24 h, that is, the substituents at the ster-
eogenic C-3 and C-7 have a major effect on the stability of
these molecules.
amines, such as phenethylamine and (pseudo)ACHTNUTRGNEeNUG phedrines,
are generally not effective for acids due to the formation of
ammonium carboxylate salts, which may not be soluble in
the NMR solvent.[17] Apart from macrocyclic receptors,[18,19]
recent development of small-molecule CSAs are dominated
by diamine and/or amide derivatives.[20–29]
Potentially, the zPHC scaffold could provide multiple sites
for dipole–dipole, hydrogen-bonding and p–p interactions,
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as was suggested by the electron distribution shown in
Figure 8. In a previous study,[30] we have shown that hetero-
cycles of type 4 possess certain basic character. Keeping this
in mind, the application of these compounds as CSAs for
chiral acids was examined in this work. The initial study was
carried out by recording 1H NMR spectra (400 MHz) of
equimolar mixtures of racemic mandelic acid (MA) as a
model analyte with 4a, 4 f, 4h or 4j at 238C. The addition of
a solution of receptor 4h (26.3 mm) to a solution of racemic
À
MA (26.3 mm) in CDCl3 caused the stereogenic C H signal
of the a-chiral acid to shift upfield and split into two equally
intense singlets. Variation of the N-Me substituent in 4h to
a bulky N-neopentyl in 4j did not induce significant changes
in the enantiodiscrimination (Figure S1 in the Supporting In-
formation). Conversely, the isopropyl- and benzyl-substitut-
ed derivatives, 4a and 4 f, respectively, were ineffective
CSAs.
To define the binding interactions, NMR titration experi-
ments were performed by using compounds 4h and 4j.[31,32]
The effect of concentration on the chemical shift differences
(DDd) was examined by the addition of 4h to a solution of
(rac)-MA (Figure 9). Baseline resolution was achieved over
Figure 10. Chemical shift non-equivalencies (DDd) of the enantiomeric a-
H signals of (rac)-MA (26.3 mm in CDCl3; spectra were recorded at
*
*
238C) as a function of molar ratio for the receptors 4h ( ) and 4j ( ).
a considerably wide concentration ratio of [4]/
G
(ca. 0.25–9.0), with (S)-MA undergoing the larger upfield
shift.
Figure 10 represents changes in the chemical shift non-
equivalence (DDd) observed for the interaction of (rac)-MA
in the presence of increasing amounts of 4h and 4j. In both
cases, the enantiomeric separation increased sharply and
maximum DDd values of 0.052 ppm (21 Hz) and 0.057 ppm
(23 Hz) were observed for 4h and 4j, respectively, near [4]/
[(rac)-MA]=2.
The stoichiometry of the donor–acceptor complex was es-
ACHTUNG-
TERNNUG
tablished by using Jobꢂs plots (see Figure S3 in the Support-
ing Information). Keeping the total concentration of [4h]+
[MA] constant at 20.3 mm, the plot of Dd versus the mole
fraction of (R)- or (S)-MAs (X) showed a maximum at X=
0.67, providing the evidence that both enantiomers of MA
form 2:1 complexes with zPHC. The binding constants of 4h
for MA were subsequently determined quantitatively, by
varying the concentration of single enantiomers of MA in
the presence of a constant concentration of 4h (Figure 11).
By using the established 1:2 complex stoichiometry, non-
linear least-squares fitting[33] revealed K(S)=(341Æ11)mÀ1
and K(R)=(176Æ5)mÀ1, corresponding to a chiral recogni-
tion energy (DDG8) of À0.39 kcalmolÀ1.[34]
Last but not least, excellent correlation between expected
and observed ee values was established by integration of the
a-proton signal of mandelic acid (ee between À85 to 85%)
in the presence of two equivalents of 4h (Figures 12 and S6
in the Supporting Information). The excellent linearity fit
showed that the method can be used to determine the enan-
tiopurity of MA with a high level of accuracy.
In a preliminary study, 4h was also employed for the
enantiodiscrimination of other types of chiral acids. We
were particularly interested in dibenzoyltartaric (or tartaric
acid dibenzoate, pKa =1.85) and camphorsulfonic (pKa =
1.2) acids, which are substantially more acidic than MA
Figure 9. Variation with concentration of DDd for (rac)-MA (26.3 mm) in
the presence of 4h (CDCl3, 400 MHz, 238C).
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K. K. Hii et al.
Figure 11. Plots of Dd for the N-Me signal of 4h (5.07 mm) as a function
*
of [MA]/
N
*
=binding with R-MA.
Figure 13. Resolution of dibenzoyltartaric acid by the addition of 4h
(20 mm in CDCl3, 400 MHz, 238C). Signals corresponding to the methine
protons are presented. a) Racemic acid; b) 4h+l-acid (100% ee);
c) 4h+d-acid (100%ee); and d) 4h+racemic acid.
Figure 12. Correlation between the prepared and observed % ee values.
(pKa =3.41). Consequently, they present a considerable chal-
lenge for CSAs that contain Brønsted basic sites (e.g.,
chiral-amine derivatives), which can form insoluble salts
with these analytes.
Addition of an equimolar of 4h to dibenzoyltartaric acid
induced an upfield shift of the methine protons (Figure 13).
In this case, the protons remained chemically equivalent in
each complex, that is, the C2 symmetry appeared to be re-
tained, at least on the NMR timescale. A chemical-shift dif-
ference of DDd=0.12 ppm (48 Hz) was subsequently record-
ed, which is significantly larger than that reported with
other CSAs derived from chiral amines.[22,23,25] To date, there
is only one CSA reported for the enantiodiscrimination of a
chiral sulfonic acid.[21] Thus, we were delighted to find that
4h can induce splitting in the C8 and C9 methyl resonances
of 10-camphorsulfonic acid (Figure 14). In this case, DDd of
0.0195 (7.8 Hz) and 0.0215 ppm (8.6 Hz) were recorded
when [acid/4h]=1:1, whereas 0.0214 (8.5 Hz) and
0.0223 ppm (8.9 Hz) were observed when the ratio was
changed to 2:1.
Figure 14. Resolution of camphor-10-sulfonic acid (17.2 mm in C6D6;
400 MHz; 238C). Resonances corresponding to C8 and C9 methyl groups
are presented. a) Racemic acid; b) 4h+racemic acid; c) 4h+R-acid
(100% ee); d) 4h+R-acid (35% ee). The signals at approximately
0.4 ppm belongs to residual water; other signals belong to the analyte.
Conclusion
A family of chiral zwitterionic phosphorus-containing het-
erocycles (zPHC) have been designed, synthesised and char-
acterised. X-ray structural analysis and DFT calculations
suggest that these zPHCs are highly polar molecules, com-
À
bining a concentration of electron density on the PO2
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from a suitable solvent. For further details, see the Supporting Informa-
tion.
moiety, with a highly diffused cation within the bisimidazo-
line framework. These special qualities were exploited in
their application as structurally new chiral-solvating agents,
in resolving a wider range of analytes. Our preliminary stud-
ies showed that they can be used to resolve an a-hydroxyl
acid, a diacid and a sulfonic acid. Examples of such broad
applicability of a CSA across different types of chiral acids
are rare. The nature of the binding will be examined in our
future work, including potential applications in asymmetric
synthesis.
Acknowledgements
A.E.S. was supported by
a Marie Curie Intra-European Fellowship
within the 7th European Community Framework Programme (FP7, proj-
ect no. 252247). I.M.L. was supported by IOCB (grant no. Z40550506)
and I.C. by the Ministry of Education of the Czech Republic (grant no.
MSM0021620857). E.V.B. is grateful to Dr. Klaus Hellgardt (ICL) for
support.
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Synthesis of phosphorus zwitterionic heterocycles 4: General procedure:
A mixture of the corresponding salt 9 (1 mol equiv) and aqueous NaOH
(10%, 15 mol equiv) in CH2Cl2 (15 mL per 1 mmol of 9) was vigorously
shaken in a separatory funnel for 5 min. The organic phase was separat-
ed; the aqueous phase was extracted with CH2Cl2 (30 mL). The combined
organic phases were washed with H2O (20 mL), dried over MgSO4 and
concentrated to dryness under reduced pressure to provide the corre-
sponding free base 3 quantitatively as a white solid. The free MBI base 3
was then dissolved in dry CH2Cl2 (5 mL per 1 mmol of salt 9), the result-
ing solution was cooled to 08C followed by the dropwise addition of
phosphorus oxychloride (1 mol equiv) and triethylamine (2 mol equiv)
under the atmosphere of dry argon. The reaction mixture was stirred for
24 h at RT, concentrated to dryness under reduced pressure and
quenched with aqueous NaOH (10%, 10 mol equiv). After 12 h of stir-
ring at RT, the reaction mixture was extracted with CH2Cl2 (3ꢃ50 mL),
the combined organic phases were washed with H2O (20 mL), dried over
MgSO4 and concentrated to afford pure inner salts 4 as white or pale
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Chem. Eur. J. 2013, 00, 0 – 0
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www.chemeurj.org
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[33] We thank Professor Christopher Hunter (University of Sheffield,
UK) for provision of the NMRTit HGG program.
[34] DDG8=ÀRTln[K(S)/K(R)]).
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Received: January 7, 2013
Published online: && &&, 0000
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Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!

New Chiral Zwitterionic Phosphorus Heterocycles
FULL PAPER
A convenient synthetic approach to a
new class of chiral zwitterionic phos-
phorus-containing heterocycles starting
from methylene-bridged bis(imidazo-
lines) was designed and executed. Sta-
bility and properties of the synthesized
compounds were investigated. The
applicability of the designed com-
pounds as chiral solvating agents for
the determination of the enantiomeric
excesses of chiral acids was demon-
strated.
Synthetic Methods
A. E. Sheshenev, E. V. Boltukhina,
A. A. Grishina, I. Cisarova,
I. M. Lyapkalo, K. K. Hii* . &&&& — &&&&
ˇ
New Chiral Zwitterionic Phosphorus
Heterocycles: Synthesis, Structure,
Properties and Application as Chiral
Solvating Agents
Chem. Eur. J. 2013, 00, 0 – 0
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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These are not the final page numbers!