Access to enantiomeric organic compounds with potential for synthesis via racemic conglomerates: Inositol derivatives as a case in point

Article abstract of DOI:10.1021/acs.cgd.1c00126

The crystal structure database was used to identify inositol derivatives that could be crystallizing as racemic conglomerates. Among the six racemic inositol derivatives identified, racemic 4-O-tosyl-6-O-benzyl-myo-inositol-1,3,5-orthoformate (A) was foun

Full text of DOI:10.1021/acs.cgd.1c00126

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Access to Enantiomeric Organic Compounds with Potential for
Synthesis via Racemic Conglomerates: Inositol Derivatives as a Case
in Point
Nivedita T. Patil, Madhuri T. Patil, Nitai Sarkar, Rajesh G. Gonnade,* and Mysore S. Shashidhar*
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ABSTRACT: The crystal structure database was used to identify inositol
derivatives that could be crystallizing as racemic conglomerates. Among the
six racemic inositol derivatives identified, racemic 4-O-tosyl-6-O-benzyl-myo-
inositol-1,3,5-orthoformate (A) was found to be a true conglomerate and was
resolved on the multigram scale by the preferential crystallization technique.
This resolution procedure does not require the use of any enantiomeric
resolving agent. The resolved enantiomers of A are useful for the synthesis of
natural and unnatural enantiomeric derivatives of inositol, since they carry
orthogonal hydroxy protecting groups. Racemic 4-O-methanesulfonyl-myo-
inositol-1,3,5-orthoformate (B) on crystallization from common organic
solvents generally yielded racemic twin crystals, while in the presence of
structural analogs as additives, they yielded true racemic crystals. A comparison of the crystal structures of the true racemate, twinned
crystal and crystal of one of the enantiomers of B, revealed the reasons for the formation of polymorphic (twin) crystals. Such
instances are relatively rarely encountered but nevertheless shed light on our understanding of polymorphism and twinning of
crystals.
Generally, a racemic compound can crystallize as racemate,
kryptoracemates (chiral racemates), conglomerate, solid
solution, or scalemic (anomalous racemates, Figure S1,
SI).17−20 Racemate crystals (90−95% of the cases) belong to
non-Sohncke space groups and contain an equal amount of
both enantiomers in regular order in the crystal lattice. In
kryptoracemate (0.8% cases), the asymmetric unit of the
crystal structure is comprised of both enantiomers (Z′ = 2 or
even numbers) in equal numbers and the racemate crystallizes
in Sohncke space groups.21 Conversely, in conglomerates (5−
10% cases), both enantiomers are spontaneously resolved and
crystallize separately. Each crystal is enantiopure, belonging to
a Sohncke space group, and the crystal structures of the two
enantiomers have a mirror symmetry relationship. The
“racemic twin” crystals are a different kind of conglomerate
crystals (lamellar conglomerate)22 wherein each crystal
comprises separate domains (lamellae) of both enantiomers
and each domain contains only one of the two enantiomers
and the crystal belongs to a Sohncke space group. In solid
solutions (1−2% cases),18,19,21 although both enantiomers are
INTRODUCTION
■
A perusal of the chemistry literature published in the last few
decades reveals the extent of effort devoted to the synthesis
and study of chiral molecular entities. Synthesis of
enantiomerically pure organic compounds and resolution of
racemates have gained unprecedented significance due to
different properties of enantiomers and racemates, e.g., the
therapeutic efficacy of drugs.1−4 Enantiomeric organic
compounds can be extracted routinely from natural sources,
although with wide variation in inputs in terms of cost, effort,
and time. Due to the high enantiomeric purity of organic
compounds isolable from natural sources, many of them form
the starting materials for the synthesis of natural and unnatural
chiral molecular entities.5−9 Most laboratory methods of
preparation of enantiomeric compounds involve the use of
enantiomeric molecular entities such as catalysts (including
enzymes) for asymmetric synthesis, chiral auxiliaries, resolving
agents, or chiral stationary phases for the separation of
enantiomers (in a racemate).3,10−14 Almost all of these
methods to obtain enantiomers depend on the solution-state
chemistry. Enantiomers present in a racemate can also be
separated by preferential enrichment of enantiomers15 and by
preferential crystallization of conglomerates.16 Interestingly,
the separation of enantiomers by such a simple crystallization
process does not require the use of any external enantiopure
entity and, hence, require relatively less effort to scale up (as
compared to chemical methods of separation of enantiomers).
Received: February 2, 2021
Revised: June 3, 2021
Published: June 15, 2021
https://doi.org/10.1021/acs.cgd.1c00126
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present in equal quantity, they are randomly distributed
(irregular arrangement of enantiomers) in the crystal lattice,
with no long-range periodicity. Solid solution can crystallize in
non-Sohncke or Sohncke space groups. In the scalemic
racemates19,21 (anomalous racemate, 37 structures are reported
in Cambridge Structural Database  CSD), the stoichiometric
ratio of the two enantiomers is other than 1R:1S. The scalemic
racemates are rarer than kryptoracemates and crystallize in
Sohncke space groups. The rare occurrence of scalemics could
be due to fewer crystallization studies from nonracemic
mixtures. Among these solid forms of racemates, several
conglomerates and few twin crystals have been resolved to
their enantiomers by crystallization techniques. Although
preferential crystallization of racemic conglomerates has the
potential to provide enantiomers rapidly, this method of
resolution has limitations in that not all racemates are solids
and only a small percentage (∼5−10%) of solid racemates exist
as conglomerates under ambient conditions.16,17,21
mixture and pure enantiopure crystals are identical.16 A survey
of the CSD 2020 (version November 2019) for the crystal
structure of inositol derivatives revealed that among 416
derivatives, 130 crystallized in Sohncke space groups. Of these
130 entries, 54 were diastereomeric derivatives of myo-inositol,
and among the 76 remaining myo-inositol derivatives, 41 were
enantiopure compounds, 28 were meso-derivatives, and 7 were
racemates (Scheme 1).36−41 A perusal of our own (unpub-
lished) crystal structure database revealed that the racemic
tosylate Rac642 crystallized in the orthorhombic Sohncke
space group P212121.
Scheme 1. Racemic Inositol Derivatives Which Are Known
to Crystallize in Sohncke Space Groups (Rac1, Rac2,
a
Rac5P21; Rac3, Rac4, Rac6, Rac7P212121)
There has been an upsurge in interest in the synthesis of
cyclitols, their phosphorylated derivatives and the associated
lipids in the recent past because of the biological roles played
by phosphoinositols in living cells.23−28 The intense biological
studies aimed at understanding the myo-inositol cycle and its
implication in several diseases led to a demand for enantiopure
synthetic inositol derivatives.29,30 Although inositol derivatives
have been prepared using a variety of starting materials,
naturally occurring myo-inositol is the most preferred starting
material because of its abundance and well-developed
chemistry.30−32 However, the limitation of this approach is
that since myo-inositol has the meso-configuration, preparation
of its enantiomeric derivatives and analogs necessitates the
resolution of racemates or the use of enantiopure catalysts and,
more often than not, tedious and labor intensive separation
and purification procedures. Since a large number of isomeric
products are generated during the derivatization of myo-
inositol,33 the majority of the known methods for the
preparation of enantiopure inositol derivatives have resorted
to the use of partially protected myo-inositol derivatives (which
have fewer hydroxy groups, such as myo-inositol orthoesters)
to generate enantiomeric derivatives.29−32,34 We realized that a
large number of inositol derivatives exist as crystalline solids
and hundreds of crystal structures were reported in the CSD.
Hence, identifying and resolving inositol derivatives that could
function as versatile synthetic intermediates by preferential
crystallization of conglomerates appeared practical. This article
reports our efforts in realizing the resolution of a racemic myo-
inositol derivative (conglomerate) into its enantiomers by
preferential crystallization.16 This approach is more or less an
absolute asymmetric synthetic approach,35 since no enantio-
pure molecular entity is used to obtain enantiomeric end
products. During this work, we also encountered a myo-inositol
derivative that exhibited polymorphism depending on the
crystallization conditions wherein one of the crystal forms was
a racemic twin and the other polymorph was a true racemate.
The significance of the study of the crystal structure of twinned
racemates is the fact that the intricacies of the twinning
phenomena could shed light on energetics and mechanisms of
nucleation and crystal formation.
a
The molecular structure of one of the enantiomers is shown for
brevity.
Among the racemic inositol derivatives which crystallized in
the Sohncke space group, Rac1−Rac4 seemed unsuitable as
versatile synthetic intermediates, while the orthoformate
derivative Rac5 revealed molecular crystal polymorphism.
One of the polymorphs was a true racemate (crystallized in
̅
triclinic P1 centrosymmetric space group), while the other
crystallized as a rarely encountered kryptoracemate43 in the
monoclinic P21 Sohncke space group, with two molecules of
the enantiomeric pair in the asymmetric unit.38 Hence, we did
not attempt to resolve Rac1−Rac5. The racemic sulfonates
Rac6 and Rac7 were amenable to synthetic transformations
due to orthogonally protected hydroxy groups (benzyl ether,
tosylate/mesylate, and orthoformate), and we had earlier used
sulfonate esters of inositol for the synthesis of several naturally
occurring inositol derivatives.44−47 Accordingly, a detailed
investigation of the crystallization behavior of Rac6 and Rac7
and their resolution by preferential crystallization of
enantiomers was pursued.
The racemic tosylate Rac6 was prepared as shown in
Scheme 2, starting from commercially available 8 in an overall
yield of 30% over five steps. The racemic tosylate Rac6 can
also be obtained in three steps from 8,42 but the synthetic
sequence shown in Scheme 2 is more suited for preparation on
a gram scale. Crystals of the tosylate Rac6 exhibited all the
characteristics of a racemic conglomerate: (a) the melting
point of a single crystal (182−184 °C) was higher than that of
a random mixture of crystals (152−154 °C); (b) the simulated
powder X-ray diffraction (PXRD) pattern from a single crystal
X-ray diffraction data and experimental PXRD pattern of a
random crystalline mixture of Rac6 were identical (Figure S2,
SI); (c) chiral HPLC analysis of a mixture of crystals showed
the presence of both enantiomers in the ratio 1:1 (Figure S3a,
SI), while that of single crystal showed the presence of a single
RESULTS AND DISCUSSION
■
Since a racemic conglomerate is a physical mixture of
enantiopure crystals, it crystallizes in a Sohncke space group,
and the powder X-ray diffraction profiles of the racemic
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a
process of resolution. However, the enantiomeric purity of
both resolved enantiomers was confirmed by chiral HPLC
analysis. The absolute configuration of the resolved enantio-
meric tosylates was established by single-crystal X-ray
diffraction analysis (anomalous dispersion effects, Flack
parameter was 0.02(6) and 0.04 (3), respectively, for D6
and L6 crystals), which showed that D6 was (+)-1D-4-O-tosyl-
6-O-benzyl-myo-inositol-1,3,5-orthoformate and L6 was
(−)-1L-4-O-tosyl-6-O-benzyl-myo-inositol-1,3,5-orthoformate.
This agrees with the fact that the known (+)-1D-2,4-di-O-
benzyl-myo-inositol (D14, Scheme 3)49 was obtained48 from
L6. The benzyl ether D14 is a precursor for the preparation of
1L-myo-inositol-1,3,4,5-tetrakisphosphate.13,49 Hence, in prin-
ciple, this constitutes a formal synthesis of the latter
enantiomeric tetrakisphosphate, without the aid of any external
optically active molecular entity.
Scheme 2. Preparation of the Tosylate Rac6
The advantage of the present method of using D6 and L6
for the preparation of enantiopure compounds is that neither
any enantiopure reagent nor the intervention of diastereomeric
derivatives is necessary to arrive at enantiopure synthons or
end products. All the previously reported approaches for the
preparation of enantiopure inositol derivatives involved
enantiopure reagents or (more often than not, chromato-
graphic) separation of diastereomeric derivatives (and
conversion of the separated diastereomers back to enan-
tiomers). Since all the functional groups (an ether, a tosylate, a
hydroxy group, and the orthoformate) in D6 and L6 are
orthogonal, these chiral derivatives have high synthetic
potential as versatile intermediates. “Absolute asymmetric
synthesis” is a term used to imply the generation of optical
activitywithout the use of any chiral agent or environment.50
Synthesis of enantiopure end products involving the resolution
of a conglomerate using a homochiral crystal as a seed for the
preferential crystallization of enantiomers is close to this
approach, since the formation of a conglomerate is an intrinsic
property of a particular racemate and does not require the use
of any external enantiopure agent or environment. The
formation of enantio-enriched molecules via reactions in chiral
crystals comprising of achiral molecules is another example of
“Absolute asymmetric synthesis”.51 Incidentally, the processes
of generation of enantiomers without the aid of enantiopure
agents are also of immense relevance to understanding the
occurrence and evolution of homochirality in nature.
a
Compounds Rac6, Rac11, and Rac12 are racemic, while 8, 9, and 10
have the meso-configuration; Bz = C6H5CO−; Bn = C6H5CH2−; Ts =
p-CH3C6H4SO2−.
enantiomer (Figure S3b, SI).48 Crystals weighing at least 1 mg
were initially obtained from a solution of Rac6 in ethyl acetate.
We could use only one of these crystals for seeding the first
crystallization experiment (during resolution), since we had no
clue about the absolute configuration of the constituent
molecules of different individual crystals. However, the fact
that Rac6 crystallized as a conglomerate guaranteed that all the
constituent molecules within a single crystal had the same
configuration (Figure S4, SI). By an iterative crystallization
procedure, we could achieve resolution of Rac6 on a gram
scale (Scheme 3, Figure S5, SI).48
We determined the visual melting range of various mixtures
of D6 and L6 and realized that this data could be used as a
guideline to follow the resolution of Rac6 by crystallization
(Tables S3−S5, SI). The melting range of the enantiomerically
enriched crystals approached 179−181 °C toward the end of
resolution by repeated crystallization. The optimum duration
for crystallization 1 was 25 min (see the Experimental Section
for details) to obtain enantiomeric ratios of 80:20 or better.
Allowing crystallization 1 to proceed for more than 25 min
resulted in reduced enantiomeric excess (Tables S4−S5, SI).
Hence, this melting range data allowed the tracking of
enantiomerically enriched samples (by measuring the melting
range) obtained during the preferential crystallization of
enantiomers from Rac6 and circumvented the need for
HPLC analysis after each crystallization step, during the
Crystal Structure of D6 and L6. Single-crystal structure
determination revealed that both enantiomers crystallized in
the frequently encountered orthorhombic Sohncke space
group P212121 containing a single molecule in the asymmetric
unit (Figure S6, SI). The crystal structure analysis showed
adamantane-like geometry for the myo-inositol orthoformate
moiety, whereas the pincer-like benzyl and tosyl groups were in
Scheme 3. Resolution of Rac6 by Preferential Crystallization of Enantiomers from a Solution in Ethyl Acetate−Acetonitrile
a
Mixture48
a
The purity of the resolved enantiomers was >99%, as revealed by chiral HPLC analysis (Figure S5, SI). The known D14 could be obtained from
L6.
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extended and folded conformation, respectively. The closely
associated molecules generated a helical architecture along the
crystallographic 21-screw axis (b-axis) through OH···OS
(O2H2A···O8) hydrogen bonding interactions (Figure 1a).
arrangement on the bc plane revealed the stitching of CH···π
linked helices through CH···O (C12H12···O3, C16
H16···O1, C21H21B···O2) interactions engaging phenyl
rings of the benzoyl and tosyl groups (Figure 1).
The approximate energy for the intermolecular potential,
which is the sum of Coulombic, polarization, dispersion, and
repulsion terms (as defined in the PIXEL method52,53 and
integrated into the program Mercury54) was calculated using
UNI force field computations. The estimation of potential
energy values for the intermolecular interactions revealed that
the molecules were strongly associated (−64.8 kJ/mol) along
the shortest a-axis (Figure 1b). The packing of molecules along
b- and c-axes were relatively weak (Figure 1b), as indicated by
potential energy values for CH···π (−29.7 kJ/mol) and O
H···OS (−26.9 kJ/mol) interactions. Along the c-axis
wherein the adjacent helices are connected through tosyl
moiety via CH···O and moderate CH···π interactions, the
intermolecular potential energy value was −44.6 kJ/mol. This
suggests that the association of the molecules along the a-axis
could have been swift (compared to those along b- and c-axes)
because of the relatively stronger binding affinity making it the
fastest growing face. This is corroborated by the needle-shaped
crystals of D6 and L6. The Bravis, Friedel, Donnay, and Haker
(BFDH) morphology study55,56 also substantiated the rod
shape of the crystal, revealing that either [101] (red) or [110]
(green) is the fastest-growing face (Figure 2).
It has also been suggested that the growth rate of a plane is
inversely proportional to the interplanar spacing, and the
growth is faster along a direction having smaller distance
spacing.55,56 Although we cannot visualize the nucleation
process, we can speculate that the association of the molecules
along the shortest a-axis (Figure 1b) to form a one-
dimensional chain could have been step-1 of the crystallization
event. The subsequent growth of these 1D polymers along the
b-axis (through OH···O and strong CH···π interactions)
(Figure 1b) could have been step-2 and packing of the
neighboring helices along the c-axis (through CH···O
contacts) could have been step-3 (Figure 1a). Hence, the
strong interactions between the homochiral molecules,
particularly along the a-axis, seem to have been responsible
for spontaneous resolution and conglomerate formation.
Crystallization Behavior of the Mesylate Rac7. The
racemic mesylate Rac7 was prepared by the mesylation of the
racemic dibenzoate Rac15 with methanesulfonyl chloride
followed by methanolysis of the two benzoates in the presence
of an excess of triethylamine.36 The enantiomeric mesylate D7
was prepared by mesylation of the known57 dicamphanate D17
followed by aminolysis of the camphanates (Scheme 4).
Crystallization of Rac7 from chloroform−methanol mixture
(1:1, v:v) at ambient conditions by slow evaporation over 3
days gave crystals (Form I, mp. 147 °C). Crystallization of
Rac7 in the presence of additives ((R)-(−)-mandelic acid or
myo-inositol-1,3,5 orthoformate, about 2% by weight) from a
1:1 mixture (v:v) of chloroform and methanol at ambient
conditions by slow evaporation over 24 h gave crystals (Form
II, mp. 139−141 °C) (Figure S7, SI). We used the additives
during the crystallization of Rac7 since we suspected that
crystallization of pure samples of Rac7 yielded twinned
crystals, while crystallization in the presence of certain
impurities yielded a true racemate. Generally, isostructural
additives are used as seeds to crystallize polymorphs,58,59
wherein the interactions between the additive and the solute
molecules aid in the enrichment of the different crystalline
Figure 1. Molecular packing viewed down the (a) c-axis and (b) a-
axis showing the linking of the adjacent CH···π helices.
Intermolecular interactions are indicated by blue (OH···O),
magenta (CH···O), and cyan (CH···π) colors. The yellow and
green strips in (a) show helices linked via OH···O and CH···π
interactions, respectively.
Another helical assembly connected the 21-screw-related
molecules along the b-axis by highly directional CH···π
(C7H7···Cg5 engaging orthoformate H atom and π cloud of
the phenyl ring of benzyl group) interactions supplemented by
a CH···O (C16H16···O1) interactions. Both these helices
are intermingled and run in a parallel fashion along the b-axis.
Adjacent CH···π linked helices are unit-translated through
OH···O and CH···O (C3H3···O5 and C5H5···O7)
interactions along the shorter a-axis to reveal a compact
packing on the ab plane (Figure 1b). The view of molecular
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Figure 2. BFDH morphology calculations of L6.
Scheme 4. Synthesis of the Racemic and Enantiomeric Mesylates Rac7 and D7
phases. In the present case, the additive myo-inositol-1,3,5
orthoformate offers some structural similarity with Rac7, but
((R)-(−)-mandelic acid does not. Hence, it is not easy to
predict how the additive molecules provided nucleation sites
for the generation of stable Form II crystals. However, we feel
that the epitaxial interaction between nucleation promoting
surface of additive and prenucleation aggregate of Form I
crystals selectively inhibits Form I nucleation and promotes
the growth of stable Form II. The enantiomer D7 was
crystallized from chloroform−methanol mixture (1:1, v/v, mp.
152−154 °C).
A bulk sample of crystalline mesylate Rac7 had a melting
point of 139−141 °C, while an isolated single crystal,
crystallized from chloroform−methanol mixture of Rac7, had
a higher melting point of 145−154 °C which suggested the
possibility of Rac7 being conglomerate crystals. DSC analysis
of Form I and Form II crystals of Rac7 and crystals of D7
showed only the melting endotherm at 143 °C, 137 °C, and
153 °C, respectively (Figure S8, SI). This indicated the
absence of phase transitions before the melting of crystals and
that Forms I and II were not thermally interconvertible. The
experimental PXRD patterns of Form I and Form II are
different and showed a good match with their respective
simulated PXRD pattern calculated from the single crystal X-
ray diffraction data (Figure S9, SI). Furthermore, chiral HPLC
analysis of individual single crystals of Rac7 (Form I) showed
that the ratio of enantiomers present in them varied from
crystal to crystal, but none was a true racemate nor homochiral
(Figure S10, SI). These results suggested that the crystals of
the racemic mesylate Rac7 (Form I) were not a true
conglomerate.
Single-crystal X-ray diffraction analysis revealed that Form I
crystals of Rac7 and crystals of D7 belonged to the
orthorhombic P212121 Sohncke space group, whereas Form
II crystals of Rac7 crystallized in the centrosymmetric
monoclinic C2/c space group, each containing one molecule
in the asymmetric unit (Figure S11, SI). The unit cell
parameters of Form I crystals of Rac7 and crystals of D7 were
identical revealing isostructurality (see Experimental Section).
However, their Flack parameter values differed (0.62(14) for
Form I and −0.07(8) for D7 crystals), indicating that the
Form I crystals could be a racemic twin (having both
enantiomers in single crystals). These results (along with DSC
and HPLC analysis) confirmed the presence of different
domains of the two enantiomers in Form I crystals of Rac7. A
comparison of the scanning electron micrographs of Form I,
Form II crystals of Rac7, and crystals of D7 revealed epitaxial
twinning in Form I crystals due to the stacking of the layers
(Figures S12−S14, SI). Form II crystals of Rac7 and crystals
of D7 contained no perforation and were evenly stacked,
resulting in the formation of block or plate-shaped crystals.
The crystal density values of Form I, Form II, and D7 were
1.735, 1.741, and 1.722 g/cm3, respectively, revealing that the
molecules in racemic crystals (Form II) were closely packed as
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Figure 3. (a) ORTEP of Rac7 (Form I) showing the numbering of atoms; (b) structural overlay of molecules in Form I (pink) and Form II
(green) crystals of Rac7.
compared to twinned (Form I) and enantiopure (D7) crystals;
the packing energy calculation also corroborates this. The
estimation of packing energy for Form I, Form II, and D7
crystals gave the values of −165.6, −177.4, and −164.1 kJ/mol,
respectively, indicating that the Form II crystals are relatively
more stable compared to Form I crystals. The results also
validate the Wallach rule, which states that molecules in
racemic crystals are packed more densely than their chiral
counterparts.60,61 These results clearly showed that Rac7 did
not crystallize as a true conglomerate.
The crystal structure analysis revealed identical conforma-
tion of molecules in Form I crystals of Rac7 and crystals of
D7, while the conformation of molecules in Form II crystals of
Rac7 was different (Figure 3 and Figure S15, SI). The
structural overlay of the molecules in polymorphs Forms I and
II of Rac7 revealed the change in the orientation of the
hydroxy and mesylate groups.
In both Form I and crystals of D7, the H atom of the 2-
hydroxy group is pointed toward the orthoformate moiety
(torsion angle, C1−C2−O2−H2A = −53.35°), whereas in the
Form II crystals, it is pointing away from the orthoformate
group (torsion angle, C1−C2−O2−H2A = 153.46°). Further,
the H atom of the 4-hydroxy group also showed significant
differences (114.67°) in conformation; in Form I, the torsion
angle C3−C4−O4−H4A was −53.98°, whereas in Form II, it
was 165.65°. Additionally, the mesylate group also displayed a
considerable conformational difference (140.07°), the torsion
angle C6−O6−S1−C8 was 72.32° and −67.75° for Form I
and Form II, respectively. These conformational differences
manifested in the dissimilar molecular arrangement leading to
polymorphism in crystals of Rac7.
In Form I crystals, molecules assemble helically along the
crystallographic 21-screw axis (b-axis) using conventional O
H···O hydrogen bonds (Figure 4a). The hydroxy group O4−
H4A donates its H atom to the other hydroxy group oxygen,
O2, to form O4−H4A···O2 hydrogen bonds. The helical
association also brings the molecules related by unit-translation
symmetry into close proximity to form O2−H2A···O4
hydrogen bonds and weak C8−H8A···O1 contacts. The
neighboring helices along the c-axis are stitched through
mesylate moieties using C8−H8B···O7, C8−H8C···O8, and
C6−H6···O7 interactions; however, the association of the
adjacent helices is relatively weak (Figure 4a). The molecular
association along the a-axis also revealed a helical assembly
formed along the b-axis through relatively weak interactions
engaging mesylate moieties using C6−H6···O7, C8−H8B···
O7, and C5−H5···O8 contacts. The unit-translated molecules
along this helix are connected via the C7−H7···O2 hydrogen
bond (Figure 4b). The neighboring helices along the longer c-
axis are connected through OH···O hydrogen bonds
involving O4−H4A and O2 moieties supported by a C4−
H4···O3 hydrogen bond to form 2D compact packing on the
ac-plane.
Form II crystal structure revealed a helical assembly of
molecules through CH···O interactions (C7−H7···O7, C6−
H6···O5, and C8−H8A···O5) across the crystallographic 21-
screw axis (yellow or green, Figure 5a). The neighboring
helices along the a-axis are stitched centrosymmetrically
through conventional O2−H2A···O4 hydrogen bonds to
generate the 2D layered assembly on the ab-plane (Figure
5a). A view of the molecular packing along the c-axis revealed
the formation of one-dimensional molecular string (yellow or
green) through conventional bifurcated OH···O (O4−
H4A···O2 and O4−H4A···O3) hydrogen bonds (blue)
supplemented by C5−H5···O3 and C3−H3···O8 interactions
(cyan). Successive molecules along the string have c-glide
symmetry. The neighboring strings along the a-axis are
centrosymmetrically stitched through O2−H2A···O4 (magen-
ta) and C8−H8B···O8 (cyan) interactions to form a one-
dimensional layered assembly parallel to the c-axis. The
adjacent layers along the a-axis are connected through C7−
H7···O7, C6−H6···O5, and C8−H8A···O5 contacts (cyan) to
have a compact packing arrangement on the ac plane (Figure
5b).
As mentioned earlier, the racemic twin structure of Form I
crystals was supported by SEM images, which revealed a
lamellar domain structure, possibly consisting of alternate
layers of two enantiomers leading to a non-racemic macro-
scopic composition. It has been assumed that the growth of the
lamellar conglomerates occurs in phases from the solution
containing an equal amount of both enantiomers.22 First,
homochiral microcrystals of both enantiomers nucleate
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Figure 4. View of molecular packing in Form I crystals of Rac7 showing the helical assemblies formed by OH···O hydrogen bonds (a) and C
H···O interactions (b). The molecular arrangement in crystals of D7 is the same as in Form I crystals. The different color used for the molecules is
only for the identification of helices.
spontaneously to serve as crystallization initiators, the seed
crystals. It is followed by the layering of both the Lemellae on
one of the crystal faces of the seed crystals, alternately to yield
the lamellar conglomerate crystals of varying thicknesses.
Hence, the number of alternating lamellae of both enantiomers
in the final crystal differ, thereby yielding the lamellar
conglomerate crystals with an unequal proportion of both
enantiomers. This could be the reason the chiral HPLC
analysis of single crystals of Form I of Rac7 showed variation
in enantiomeric excess. This has also been supplemented by
determining the Flack parameter (0.62(14)) of the single
crystal using single-crystal X-ray diffraction.
The lamellar structure appeared along the slowest growing
face of the crystal (transverse to the plate, along the longer c-
axis), revealing a weak association between both enantiomers.
Face indexing of the lamellar crystals (Figures S16−S18, SI)
showed it to be the (001) face. In an attempt to gain better
insight into the twin growth, we compared the energy values of
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Figure 5. View of molecular packing in Form II crystal of Rac7 (a) down c-axis; (b) down b-axis. The molecules are densely packed in (b) using
OH···O (blue and magenta) hydrogen bonds and several CH···O (cyan) contacts.
intermolecular interaction potentials between neighboring
molecules in dimorphs of Rac7. The energy values for the
intermolecular potential were calculated using UNI force field
computations.52,53 The estimation of the intermolecular
potential energies54 for the strongest molecular pairs in
Forms I and II revealed that the robust pairwise interaction
between molecules in Form II crystals was a centrosymmetric
OH···O hydrogen bonding interaction (O2−H2A···O4,
−52.0 kJ mol−1), which is significantly stronger than any
pairwise interaction in Form I crystals. A closer look at both
enantiopure crystals of D7 and racemic (Form II) crystal
structures indicated that the centrosymmetric OH···O
hydrogen bonding interaction might have led to the formation
of the junction between the two enantiomers and is possibly
the crucial association in the early nucleation steps that lead to
the twin boundary. According to Parsons,62 the twinning is
generally observed if the intermolecular interactions across the
twin boundary are energetically competitive with that observed
in single crystals.22,62 The longer c-axis in Form I crystals could
be due to the weak association of the molecules through C
H···O interactions involving mesylate moieties. The possible
association of molecules of both enantiomers along the twin
boundary in Form I crystals is depicted in Figure 6.
CONCLUSIONS
■
The existence of enantiomeric compounds was first realized
due to the process of spontaneous resolution and conglom-
erate formation.63−66 Separation of enantiomers from racemic
conglomerates has been used for the preparation of active
pharmaceutical ingredients,67,68 and instances of resolution of
conglomerates of certain organic compounds are reported in
the literature, but the enantiomeric products obtained had very
limited utility in organic synthesis.69−71 However, this
approach has been underutilized for the multistep organic
synthesis of enantiomeric organic compounds (natural
products and analogs, compounds of biological relevance or
significance, etc.). As illustrated in the present work with
inositol derivatives, identification of multifunctional organic
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Figure 6. Depiction of the possible boundary between S (green) and R (red) enantiomorphs of Rac7 in Form I crystals. The association is shown
along the longest c-axis. The strong centrosymmetric pairs found in Form II are located in the yellow overlap region. Blue dashed lines indicate
close OH···O hydrogen bonds between the two enantiomers. The unit cells of both enantiomers of Form I were overlapped to reveal the
possible junction in the lamellar twin crystals.
Table 1. Crystal Data Table
Crystal Data
D6
L6
Rac7, Form I
Rac7, Form II
D7
Crystal system
Formula
Molecular weight
Crystal Size
Space group
a (Å)
b (Å)
c (Å)
α (deg)
β (deg)
orthorhombic
C21H22O8S
434.44
0.51 × 0.28 × 0.18
P212121
6.1403(2)
17.4424(6)
18.0617(6)
90
orthorhombic
C21H22O8S
434.44
0.43 × 0.22 × 0.15
P212121
6.2115(17)
17.488(5)
18.342(5)
90
orthorhombic
C8H12O8S
268.24
0.35 × 0.32 × 0.25
P212121
6.1053
6.4741
25.977
90
90
monoclinic
C8H12O8S
268.24
0.45 × 0.32 × 0.21
C2/c
21.469(12)
8.978(6)
11.756(8)
90
115.431(3)
90
orthorhombic
C8H12O8S
268.24
0.45 × 0.32 × 0.21
P212121
6.1039
6.5048
26.0647
90
90
90
90
90
90
90
γ (deg)
V (Å3)
90
1934.44 (11)
4
1.492
1992.4 (9)
4
1.448
1026.8(2)
4
1.735
2046.5(2)
8
1.741
1034.89(3)
4
1.722
Z
D
calc, gcm−3
μ, mm−1
F(000)
0.217
912
0.210
912
0.347
560
0.348
1120
0.345
560
ab correct
multiscan
0.928/0.958
28.325, 100%
28057
4828
4658
h = −8, 8
k = −23, 23
l = −24, 24
0.0321
multiscan
0.860/0.975
29.995, 100%
16881
5786
5288
h = −8, 6
k = −24, 24
l = −25, 25
0.0456
multiscan
0.8881/0.9182
25°, 100%
6730
1776
1730
h = −6, 7
k = −7, 7
l = −28, 30
0.0551
multiscan
0.8589/0.9304
25°, 100%
7873
1809
2024
h = −25, 25
k = −10, 10
l = −13, 13
0.0490
multiscan
0.8466/0.8688
25°, 99.9%
7215
1827
1782
h = −8, 7
k = −7, 7
l = −30, 26
0.0651
Tmin/Tmax
2θmax, deg
Total refln.
Unique refln.
Obs. refln.
h, k, l
Rint
No. of parameters
R1 [I > 2σ]
273
0.0290
273
0.0377
157
0.0402
157
0.0308
157
0.0283
wR2 [I > 2σ]
R1 [all data]
0.0703
0.0302
0.0953
0.0424
0.1169
0.0425
0.0806
0.0408
0.0693
0.0289
wR2 [all data]
Goodness of fit (S)
Δρmax (e A−3), Δρmax
Flack Parameters
CCDC No.
0.0709
1.054
0.305, −0.312
0.02(6)
1875351
0.0987
1.025
0.254, −0.348
0.04(3)
1875355
0.1235
1.038
0.321, −0.336
0.62(14)
2055199
0.0833
1.069
0.236, −0.416
-
2055198
0.0696
1.070
0.221, −0.259
−0.07(8)
2055200
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compounds that crystallize as conglomerates, their resolution
by preferential crystallization, and their development as chiral
pool molecules is an approach worth investigating and/or
pursuing. This approach seems practical due to the recent
swelling of the crystal structure database. There have been
attempts at using readily available myo-inositol as a starting
material for the synthesis of natural products and their
analogs.34 As mentioned earlier, perhaps the main limitation
for this was the nonavailability of enantiopure inositol
derivatives in relatively large amounts; the method described
herein circumvents this lacuna. The presence of an unequal
proportion of the two enantiomers as in crystals Form I of
Rac7 is due to energetically competitive intermolecular
interactions between the two enantiomers across the twin
boundary. Although this twinning of crystals can be viewed as
an obstacle to the resolution of racemates by crystallization, the
crystal structure data helps understand the nonformation of
true conglomerates.
(Form I), Rac7 (Form II), D7, and D18 along with
interaction table; PXRD data for Rac6 and Rac7; DSC
data for Rac7 (Form I), Rac7 (Form II), and D7; SEM
images for Rac7 (Form I), Rac7 (Form II), and D7
(PDF)
Accession Codes
CCDC 1875351, 1875355, and 2055198−2055201 contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/
data_request/cif, or by emailing data_request@ccdc.cam.ac.
uk, or by contacting The Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
Rajesh G. Gonnade − Physical and Materials Chemistry
Division, National Chemical Laboratory, Pune 411008,
India; Academy of Scientific and Innovative Research,
Ghaziabad, Uttar Pradesh 201002, India; orcid.org/
0000-0002-2841-0197; Phone: +91-20-25902225;
Email: rg.gonnade@ncl.res.in
Mysore S. Shashidhar − Division of Organic Chemistry,
National Chemical Laboratory, Pune 411008, India;
Academy of Scientific and Innovative Research, Ghaziabad,
Uttar Pradesh 201002, India; orcid.org/0000-0002-
8477-1149; Email: ms.shashidhar@ncl.res.in
EXPERIMENTAL SECTION
■
Resolution of the Tosylate Rac6. Seed crystals of the individual
enantiomers D6 and L6 were available to us from previous work.48
The two enantiomers were mixed in various proportions, and the
melting range of the mixtures was determined. This data could be
used to estimate the extent of enantiomeric enrichment or resolution
achieved in individual crystallization experiments. Table 1 contains
the crystallograpic data.
Three Gram Scale Resolution. Crystallization 1. The racemic
tosylate Rac6 (3 g) was suspended in a mixture of ethyl acetate (50
mL) and acetonitrile (10 mL) and stirred at 50−60 °C to obtain a
clear solution. To this clear warm solution, crystals of the enantiomer
D6 (0.03 g) were added and stirred (at 450 rpm) for 25 min, while
the solution was allowed to cool in the air. The precipitated crystals A
were filtered (0.24−0.25 g); the range of melting point of enriched
samples was between 165 and 175 °C; the ratio of enantiomers was in
the range ∼80:20−90:10 (as revealed by the melting range, Tables
S3−S5, SI). The mother liquor was evaporated to dryness under
reduced pressure to obtain a solid A (2.5−2.6 g).
Crystallization 2. The solid A obtained above was mixed with
Rac6 (0.24−0.25 g, to make up to 3 g) and subjected to fractional
crystallization as above (using the seed crystals of L6) when the
enriched crystals B were obtained (0.24−0.25 g); the range of
melting point of enriched samples were between 165 and 175 °C; the
ratio of enantiomers were ∼20:80−10:90 (as revealed by the melting
range, Tables S3−S5, SI).
These crystallization experiments 1 and 2 were repeated nine times
each (total of about 7 g of Rac6 was used in 18 crystallization
experiments) to accumulate crystals A and crystals B (2.45 g each)
enriched with the two enantiomers D6 and L6.
Authors
Nivedita T. Patil − Division of Organic Chemistry, National
Chemical Laboratory, Pune 411008, India; Academy of
Scientific and Innovative Research, Ghaziabad, Uttar
Pradesh 201002, India
Madhuri T. Patil − Division of Organic Chemistry, National
Chemical Laboratory, Pune 411008, India; PG Department
of Chemistry, MCM DAV College for Women, Chandigarh
160036, India
Nitai Sarkar − Division of Organic Chemistry, National
Chemical Laboratory, Pune 411008, India; Academy of
Scientific and Innovative Research, Ghaziabad, Uttar
Pradesh 201002, India
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.cgd.1c00126
Crystallization 3. Crystals A (2.45 g) were dissolved in ethyl
acetate (45−60 mL), and the solution was allowed to stand open to
the atmosphere for about 12 h. The crystals of D6 obtained (1.96 g)
were filtered and stored under reduced pressure to remove traces of
solvents; mp. 178−182 °C; 25[α]D = +1.98°. The enantiomer L6
(1.95 g) was obtained from crystals B as above; mp. 178−182 °C;
25[α]D = −1.72°. The enantiomeric purity of the resolved enantiomers
(>99%) was confirmed by chiral HPLC analysis (Figure S5, SI).
Author Contributions
The manuscript was written through the contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Funding
This work was supported by an Emeritus Scientist grant
(21(1090)/19/EMR-II) to MSS from CSIR, New Delhi, India.
Notes
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.cgd.1c00126.
■
The authors declare no competing financial interest.
sı
ACKNOWLEDGMENTS
■
Experimental details for the preparation of Rac6, D7,
D13, D14, and D18 along with relevant compound
characterization data; HPLC profiles for Rac6, D6, L6,
and Rac7, and crystal structure data for D6, L6, Rac7
NTP and MTP are recipients of fellowships from CSIR, New
Delhi; NS is a recipient of fellowships from UGC, New Delhi.
This work was supported by an Emeritus Scientist grant
(21(1090)/19/EMR-II) to MSS from CSIR, New Delhi, India.
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