Bis(mandelato)borate: An effective, inexpensive spiroborate anion for chiral resolution

Article abstract of DOI:10.1039/c5cc04977f

Bis(mandelato)borate [B(Man)₂]^- (R- or S-) anions are simply prepared and appear widely effective for resolution of racemic cations. Three examples demonstrate their scope; the alkaloid tetrahydropalmatine (THP), 1,2-diaminopropane (1,2-dap) and the metal-organic complex [Co(phen)₃]³⁺ are readily resolved, either by a facile one-pot procedure, or via counter-ion metathesis.

Full text of DOI:10.1039/c5cc04977f

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Commun., 2015, DOI: 10.1039/C5CC04977F.
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DOI: 10.1039/C5CC04977F
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bis(Mandelato)borate: An Effective and Inexpensive
Spiroborate Anion for Chiral Resolution
Lawrence W-Y. Wong,a Jack W-H. Kan,a Thanh-ha Nguyen,a† Herman H-Y. Sung,a
Dang Li,a Alex S-F. Au-Yeung,a Rajpal Sharma,b Zhenyang Lina and Ian D. Williamsa*
Received 16th June 2015,
Accepted 00th August 2015
DOI: 10.1039/x0xx00000x
www.rsc.org/
bis(Mandelato)borate [B(Man)2]- (R- or S-) anions are simply
prepared and appear widely effective for resolution of racemic
cations. Three examples demonstrate their scope; the alkaloid
tetrahydropalmatine (THP), 1,2-diaminopropane (1,2-dap) and the
metal-organic complex [Co(phen)3]3+ are readily resolved, either
by a facile one-pot procedure, or via counter-ion metathesis.
Fig 1. Preparation of 1-R [Na][B(R-Man)2]
A frequent stumbling block in modern organic chemistry is the
need for enantiomeric resolution. The prevalence of chiral
compounds in modern pharmaceuticals means the industrial
availability of key enantiopure starting reagents for chiral
building blocks is of great commercial value.1
The selective crystallization of diastereomeric solids offers
one of the best resolution methods, applicable to scale-up.2 The
classical method of resolving molecular cations or anions is the
formation of diastereomeric salts.3 An analogous method for
neutral molecules through chiral co-crystal formation4 or host-
guest inclusion5 is a rapidly developing area.
Traditionally racemic mixtures of cations have often been
resolved using anions based on tartrates, mandelates6 or their
esters. Notable efforts to develop synthetic anions with high
chiral discriminating power for resolution include the
TRISPHAT anions [P(O2C6Cl4)3]- of Lacour,7 based on non-
labile tris-chelation of substituted catecholates. These have
been shown to be of good efficiency in a wide variety of chiral
resolutions, for example of metal complexes8 and dyes,9 but
remain relatively expensive. Boron is capable of chelation of
various diols, acid-alcohols, catechols and salicylic acids to
form spiroborate anions which can have a variety of uses.10
Some, such as bis(catecholato)borate [BCat2]-, have been
demonstrated to be effective crystallizing anions.11
The resolution of several common racemic amines was also
reported by Periasamy12 based on borate esters of BINOL.13
Despite this promising work the use of spiroborates for
resolution has not gained much momentum, though these
anions have been reinvestigated14 and resolution using a chiral
diborate has been recently demonstrated.15 One issue is that
unlike the octahedral tris-phosphates, the chiral borate centres
are labile and prone to racemization. Use of ligand based
chirality, as in the BINOL case, is thus necessary.
We reasoned that bis(mandelato)borate anions [B(Man)2]16
which have been recently applied to chiral ionic liquids17 and as
anti-fungal wood preservatives18 might also have promise as
resolving agents. They can be readily prepared and isolated as
simple salts such as Na[BS(R-Man)2], 1-R.‡ (Fig 1)
Herein their use in resolving racemic cation mixtures via
metathesis crystallizations, or even through facile one-pot
procedures is described. Three disparate examples (Fig 2) are
given to illustrate the variety and effectiveness of the system
which requires only boric acid, R- or S-mandelic acid and a
reasonably polar or protic solvent, such as methanol. The first
system presented is tetrahydropalmatine (THP), an isoquinoline
alkaloid of which the S-(-)-isomer is a dopamine antagonist,19
has promise as an anxiolytic20 and for treatment of addiction.21
Fig 2 Three cations resolved by [B(R-Man2] : [THP-H]+, [1,2-dap-H2]2+ and [Co(phen)3]3+
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The compound occurs in a number of plants especially in certain
Cordyalis and Stephania genera,22 frequently in racemic form, which
like the related berberine is commercially available in kg quantity.
A resolution based on the benzoyltartrate ester salt of [THP-H]+ has
been established, but the method is not optimal.23
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DOI: 10.1039/C5CC04977F
Resolution of THP can be readily achieved through stirring
Na[B(R-Man)2] 1-R with rac-THP at reflux in methanol for 3h.
Crystals of [S-THP][BS(R-Man)2] 2-R form in 80% yield upon
cooling. Chiral HPLC indicated the enantiopurity of the THP in the
solid from this initial crystallization was between 94-97% ee. A big
advantage of the mandelate system is that both R- and S- mandelic
acids are inexpensive and readily available; thus 2-S crystals can be
similarly obtained by employing S-mandelic acid in the formation of
the sodium salt. The segregation of the THP enantiomers between
the solid and solution phases can be close to complete, as shown by
the circular dichroism spectra taken from solutions based on
dissolved solid and the residual solution. The [THP-H]+ cations are
non-planar and possess an asymmetric condensed ring system the
molecular twist of which would appear to pack more favourably with
one [B(Man)2]- ion rather than the other, Fig 3.
Fig 4. Asymmetric unit of 3-R & role of methanol solvate in 1,2-dap resolution.
This compares favourably with the classic resolution of 1,2-dap
using tartaric acid, which involved a tedious number of
recrystallizations.24 In this case of 3-R the methanol has a
crucial role in the structure as a double hydrogen bond acceptor
from the 1,2-dap-H2 dication (Fig 4). Resolutions using other
solvents are possible, though details differ and in this system
the diastereomeric salt can be a contaminant, or a major
product, depending on the solvent used. The resolution of THP
can also be carried out by a similar one-pot procedure to 1,2-
The second example presented here is a rather different
challenge; 1,2-diaminopropane is a small difunctional molecule
possessing a chiral centre with -H and -CH3 groups which can
be challenging to discriminate between in solid state molecular
packing arrangements. In this case we can use a facile one-pot
procedure to give effectively complete resolution. Rac-1,2-
diaminopropane, boric acid and R-mandelic acid were heated
in methanol for 3 h followed by slow cooling to ambient
temperature. Crystals of 3-R [R-1,2-dap-H2][BS(R-Man)2]
.MeOH are formed phase pure in 80% yield. High enantiopurity
of the 1,2-dap within a crystal of 3-R is indicated since the H
and CH3 positions show no apparent site disorder. HPLC of the
bis-benzamide of the 1,2-dap derived from 3-R showed a
93.7% ee from this single crystallization step.
dap, but gives products polymorphic to 2-R and 2-S
.
The third example selected shows the resolution of
octahedral  and  metal-organic coordination enantiomers of
the well-known tris-1,10-phenanthroline cobalt(III) cation
[Co(phen)3]3+. This offers a different resolution scenario from
the previous two examples, in that shape alone is involved and
the cations have no hydrogen bond donors to interact with the
spiroborate anions. In this system a highly efficient enantio-
separation can be obtained using a metathesis procedure.
Heating a solution of rac-[Co(phen)3]Cl3 with 3 equivalents of
Na[B(R-Man)2] 1-R for several hours followed by slow cooling
back to room temperature leads to precipitation of orange
crystals 4-R, whilst still leaving an orange solution. The crystal
structure of 4-R reveals that it is a 1:3 salt of idealized formula
[(Λ)-Co(phen)3][Bs(R-Man)2]3.2MeOH. The asymmetric unit
has three independent trications, nine [BMan2]- anions and sites
for six MeOH. One site is split and disordered about a 2-fold
axis and is partially occupied and/ or hydrated.The geometry of
the anions is closely preserved in as shown in Figure 5.
Fig 3. An ion pair from the crystal structure of 2-R [S-THP][BS(R-Man)2].
Fig 5. Overlay of the nine crystallographically independent anions in 4-R
.
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DOI: 10.1039/C5CC04977F
150
100
50
0
350
400
450
500
550
600
-50
-100
-150
Fig 8. Comparison of “twisted” [BR(S-Man)2]- and “V-shaped” [BS(S-Man)2]- anions
Fig 6. Circular dichroism spectra of resolved 4-R and 4-S [Co(phen)3][B(Man)2]3
However the degree to which the enantio-separations were
attained was still mildly surprising and might indicate an
additional factor is at play.
The circular dichroism (CD) spectra of the dissolved salts 4-R
and 4-S obtained from different crystallizations employing R-
Man and S-Man respectively, are shown in Figure 6.
Comparison with literature values of [Co(phen)3]3+ complexes
indicates that ee of 90% have been obtained. It is worth noting
that in this case isolation of the salt is just greater than 50%
yield limiting the ee of the resolved salt, since dynamic
equilibrium between the  and Λ-cations will be minimal.25
Crystallization of a wide range of counter cations using the
bis(mandelato)borate anions may be facilitated in part by their
semi-rigid nature; they have two independent degrees of
freedom on the two Ph dihedral angles and displacement of the
B atom of up to 0.12Å from the chelate plane introduces a
hinge angle in the 5-membered chelate rings that can modify
the molecular shape by displacements of up to 2Å. Metathesis
appears most effective in polar and protic solvents such as
MeOH, MeCN and EtOH for which the RT solubility of
Na[B(Man)2] 1-R varied from around 1M to 0.4M. As
indicated in the examples here the choice of solvent can play a
critical role and it should be noted that for some systems we
have observed gel formation rather than crystallization.
Remarkable resolution enhancements have been achieved
by the ‘Dutch method’ of the addition of one or more resolving
ions from within the same molecular family.26 A suggested
mechanism of this non-intuitive result is that the ‘foreign’ ions
may serve to suppress nucleation of diastereomeric salts.27 In
this respect it is of interest that chelation of asymmetric ligands,
such as mandelate, creates a stereochemical centre at boron.
Density functional theory (DFT) calculations imply there is
little energetic difference in the resulting BR- and BS-
diastereomers, though they have quite different shape (Fig 8).
In the case of [B(R-Man)2]- the ‘twisted’ BS anion is favoured
by just ca. 0.5 kcal mol-1 in MeOH over the ‘V-shaped’ BR
anion, although it is exclusively preferred in the solid state for
all salts studied to-date. However the presence of the BR-
anions in solution may play a ‘Dutch resolution’ role. The ions
in Fig. 8 are still identical in shape for half the molecule, so the
BR-ions may disrupt nucleation for the two possible BS-
diastereomeric salts. If this occurs to a different extent in each
case, the resolving efficiency of [BMan2]- should be improved.
In summary we have presented evidence that
bis(mandelato)borate anions show promise as widely applicable
resolving agents. The systems presented here include 1:1, 1:2
and 1:3 salts with different cation charge, size, shape and
functionality. The [B(Man)2]- anions can be readily prepared
and isolated for use in metathesis crystallizations as simple
salts, or can be generated in situ in facile one pot resolutions
without need for prior isolation. They are equally available in
both hands and significant solubility differences for their
diastereomeric salts can lead to facile and quantitative enantio-
separation after a single crystallization step. Apart from smaller
lab scale separations these systems would also appear to have
many ideal characteristics for industrial scale-up. The authors
are grateful to Research Grants Council Hong Kong for support
of this work through grant 605511.
The effectiveness of chiral resolutions in these salts is no
doubt greatly attributable to the shape differentiation of the
[BS(R-Man)2]- and the mirror image anion [BR(S-Man)2]- ions,
which are overlayed for comparison in Figure 7. It is thus
reasonable that resulting diastereomeric salts of one such anion
with racemic cations may have reasonably differing packing
efficiencies and solubilities.
Notes and references
‡ Experimental details of synthesis and characterization data,
powder X-ray diffractograms, chiral HPLC chromatograms,
circular dichroism (CD) spectra, DFT calculations and single-
crystal X-ray structure determination summaries available in
Electronic Supplementary Information.
Fig 7. Shape differentiation of [B (R-Man)2]- (red) and [B (S-Man)2]- anions.
S
R
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