Solid phase deracemization of an atropisomer

Article abstract of DOI:10.1021/acs.cgd.7b01180

The scope of Viedma ripening and temperature cycling with respect to chiral molecules has remained mostlylimited to molecules with a single stereogenic center, while racemization proceeds through inversion at that particularstereocenter. In this article we demonstrate for the first time that atropisomers, chiral rotamers that possess an axis of chirality, can be successfully deracemized in the solid phase by either applying temperature cycling or Viedma ripening.

Full text of DOI:10.1021/acs.cgd.7b01180

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Article
Solid Phase Deracemization of an Atropisomer
Anthonius H. J. Engwerda, Pim van Schayik, Henjo
Jagtenberg, Hugo Meekes, Floris P.J.T. Rutjes, and Elias Vlieg
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.7b01180 • Publication Date (Web): 13 Sep 2017
Downloaded from http://pubs.acs.org on September 23, 2017
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Solid Phase Deracemization of an Atropisomer
Anthonius H. J. Engwerda,a Pim van Schayik,a Henjo Jagtenberg,a Hugo Meekes,*,a Floris P. J.
T. Rutjesa and Elias Vliega
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AUTHOR ADDRESS
a Institute for Molecules and Materials
Radboud University
Heyendaalseweg 135, 6525 AJ Nijmegen (The Netherlands)
KEYWORDS
chirality • atropisomer • deracemization • rotamer • Viedma ripening
ABSTRACT
The scope of Viedma ripening and temperature cycling with respect to chiral molecules has
remained mostly limited to molecules with a single stereogenic center, while racemization
proceeds through inversion at that particular stereocenter. In this article we demonstrate for the
first time that atropisomers, chiral rotamers that possess an axis of chirality, can be successfully
deracemized in the solid phase by either applying temperature cycling or Viedma ripening.
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INTRODUCTION:
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Single chirality is a key signature of living organisms and hence of utmost importance to the
development of new drugs in the pharmaceutical industry. Obtaining molecules in an
enantiopure way can however be troublesome, since straightforward synthesis typically yields a
racemic mixture of both enantiomers. Viedma ripening is a process that converts a saturated
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slurry of crystals of a racemic conglomerate into an
R
enantiopure end state by applying vigorous grinding.
The first example of this process involved achiral
sodium chlorate, which crystallizes in a chiral
fashion1. Later studies have shown that this
deracemization process can also be applied to
intrinsically chiral molecules, such as amino acid
derivatives2, but also to the enantioselective
synthesis of small molecules3, 4. Most of these
examples have focused on chiral molecules that
exhibit an sp3 hybridized carbon atom as a chiral
O
R
HN
S
N
O
Me
N
Chiral
axis
N
Me
2: R = OH
3: R = PPh2
1
Figure 1: Telenzapine (1) is an example
of an atropisomer drug, while BINOL (2)
and BINAP (3) are chiral ligands often
used in transition metal complexes.
center5. Notable exceptions include the work of the Hakansson group which involves a chiral
transition state metal complex6, and one from our own group where the chiral center is a sulfur
atom7. Other important classes of chiral compounds also exist, but have remained unexplored
with regard to Viedma ripening.
One such class concerns atropisomers, nonꢀplanar molecules that display chirality through the
hindered rotation around a single bond, which in many cases can be overcome by raising the
temperature. Atropisomers can be very stable, however, as is shown by the fact that quite a
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number of natural products exist as atropisomers, featuring only one of the two possible
enantiomers8. In addition, atropismerism is a common feature in some drugs as well. An example
is Telenzepine (1, Figure 1), an antisecretory drug of which the (+)ꢀatropisomer is the most
active form9. In addition, axially chiral molecules such as BINOL (2, 1,1ꢀbinaphthaleneꢀ2,2ꢀdiol)
and BINAP (3, 2,2'ꢀbis(diphenylphosphanyl)ꢀ1,1'ꢀbinaphthalene) are often used as ligands in
transition metal based asymmetric synthesis10. Here, we report the deracemization of the
atropisomer 4,6ꢀdimethylꢀ1ꢀ(naphthalenꢀ1ꢀyl)pyrimidineꢀ2(1H)ꢀthione (4, Figure 2) using
Viedma ripening or temperature cycling.
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RESULTS AND DISCUSSION:
Compound 4 was selected
since it crystallizes as a
racemic
conglomerate,
which is a prerequisite for
Figure 2: Atropisomer 4 crystallizes as a racemic conglomerate and
Viedma
ripening.
In
spontaneously racemizes at elevated temperatures in apolar solvents.
addition, this compound
racemizes swiftly in apolar solvents at elevated temperatures (t1/2 = 4 min in xylene at 50 °C),
whereas racemization at room temperature in polar solvents is negligible11. Racemization takes
place relatively easily since it proceeds via a reversible ringꢀopening and closingꢀmechanism12,
rather than via rotation around the chiral axis. Fujita and coworkers already showed that total
spontaneous resolution can be achieved for this compound11, 13. By slowly cooling a stirred,
saturated solution of compound 4, seeded with enantiopure crystals, they obtained an
enantiomeric excess (ee) of up to 90%. A drawback of these experiments is that the
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deracemization was achieved only on small scale (50 mg). In addition, such total spontaneous
resolution experiments need to be carried out in a carefully controlled manner, or crystallization
of the unwanted enantiomer will take place. We here investigate whether alternative methods can
be used to deracemize a racemic mixture of compound 4. Viedma ripening is a technique that
can be applied on a much larger scale14. In addition, it starts from a racemic suspension of
crystals, making it a more robust method since unwanted crystallization of the other enantiomer
is no problem15. As an alternative, we also investigated the possibility of deracemization using
temperature cycling16.
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Viedma ripening experiments:
Viedma ripening experiments on compound 4 resulted in an ee of around 90% (see experimental
part) with and without using a chiral bias.
Deracemization typically took 15ꢀ20 days
at 60 °C. We found that the outcome of
the Viedma ripening experiments is
stochastic. Out of a total of six
experiments (starting from completely
racemic conditions), three experiments
yielded the (Ra)ꢀ and three the (Sa)ꢀ
enantiomer. This is in contrast to
previous examples of Viedma ripening,
where often a bias was found for one
Figure 3: Deracemization curves of compound 4 using
temperature cycling, Viedma ripening and sonication. In
these experiments, a small initial ee was created by
adding less than 1% enantiopure material.
chiral end state, caused by the presence of chiral impurities17. Apparently this system is very
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pure or insensitive towards a bias from impurities. When applying a small initial bias (by adding
less than 1% enantiopure material), deracemization could be achieved in 15 days (Figure 3).
During the filtration, the samples rapidly cooled down, resulting in additional crystallization of
both enantiomers. This is most likely the reason why the measured ee was 90%, while the actual
value at the end of the deracemization should be (close to) 100%.
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Sonication experiments:
In order to decrease the time required for deracemization, we evaluated different experimental
configurations. Sonication of such a crystal suspension can also result in deracemization18, 19 and
Noorduin et al. have shown that this can greatly enhance the deracemization speed18. By
replacing the magnetic stirrer with a sonication bath, and starting from a small initial bias,
deracemization could indeed be achieved (Figure 3). Since no experiments without an initial bias
were performed, nothing can be said about the stochasticity of this process. The drastic decrease
in deracemization time as described by Noorduin et al. was however not observed. Since
racemization, solubility and sonication energy20 are not a limiting factor here, this could possibly
be due to a different hardness of the crystals, although no definite explanation can be given based
on the current experiments.
Temperature cycling experiments:
Recently, the groups of Flood and Coquerel described temperature cycling of a suspension of
conglomerate forming crystals as an alternative method of deracemization16, 21. In this process,
the suspension is subjected to periodic heatingꢀcooling cycles, resulting in solid phase
deracemization22. By cycling the temperature between 65 and 55 °C (again with an initial bias),
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deracemization of 4 could also be achieved (Figure 3). The time required for deracemization
under these conditions is not greatly different from that of the Viedma ripening experiments.
Temperature cycling and Viedma ripening are however difficult to compare because of the
different conditions (temperature, glass beads). In addition, the technique and temperature profile
of the cycles have not been optimized for this specific system23.
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CONCLUSION:
In conclusion, we have successfully demonstrated the first example of the deracemization of an
atropisomer using both Viedma ripening and temperature cycling at gram scale. Both methods
enabled deracemization in 15ꢀ20 days at elevated temperatures.
EXPERIMENTAL SECTION:
Synthesis of 4,6ꢀdimethylꢀ1ꢀ(naphthalenꢀ1ꢀyl)pyrimidineꢀ2(1H)ꢀthione (4):
Ammonium thiocyanate (2.0 g, 26 mmol) was added to 100 mL acetone (100 mL), followed by
the dropwise addition of benzoyl chloride (3.0 mL, 26 mmol). The resulting suspension was
refluxed for 20 min and then allowed to cool to room temperature. Next, 1ꢀnaphthaleneamine
(2.5 g, 17.5 mmol) was added and the mixture was refluxed for 1 h. The solution was poured into
water (300 mL) and the resulting residue was filtered off. The precipitate was washed with water
and added to 5% aqueous NaOH (100 mL). The suspension was heated to 80 °C for 30 min and
then cooled to room temperature. 1M aqueous HCl was added after which the pH was adjusted to
9 by adding aqueous saturated Na2CO3. The residue was filtered off, washed with water and
dried in air to yield 1ꢀ(naphthalenꢀ1ꢀyl)thiourea as a white powder in quantitative yield.
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This product was added to ethanol (50 mL), followed by the addition of 2,4ꢀpentadione (2.5 mL,
24 mmol). Next, 5M aqueous HCl (20 mL) was added and the mixture was refluxed for 3 h. The
mixture was added to icewater containing NaOH (2.5 g). The product was extracted using DCM
and dried with MgSO4. The solvent was removed after which a thick red oil was formed. Upon
addition of small quantities of acetone, product 4 precipitated as a yellow/orange powder in 52%
yield.
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1H NMR (400 MHz, CDCl3): ꢀ 7.97ꢀ7.90 (m, 2H), 7.60ꢀ7.55 (m, 1H), 7.54ꢀ7.44 (m, 2H), 7.41ꢀ
13
7.38 (m, 1H), 7.38ꢀ7.35 (m, 1H), 6.59 (s, 1H), 2.48 (s, 3H), 1.89 (s, 3H). CꢀNMR (100 MHz,
CDCl3): ꢀ 184.9, 169.9, 158.3, 137.6, 134.6, 129.6, 128.8, 128.0, 127.8, 126.9, 125.8, 125.1,
121.2, 110.8, 25.0, 21.5
Viedma ripening experiments:
Compound 4 (800 mg), glass beads (5 g, Ø ca. 2 mm VWR international), an oval PTFEꢀcoated
magnetic stirring bar (L 20 mm, Ø 10 mm) and toluene (10 mL) were added to a roundꢀbottom
flask to which a condenser was attached. The vial was heated to 60 °C and stirred at 600 rpm.
Samples were taken regularly.
Sonication experiments:
Compound 4 (800 mg), glass beads (5 g, Ø ca. 2 mm VWR international) and toluene (10 mL)
were added to a roundꢀbottom flask. The flask was sealed and placed inside a sonication bath
(35kHz, 320W) at 60 °C. Samples were taken regularly.
Temperature cycling experiments:
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Compound 4 (800 mg), an oval PTFEꢀcoated magnetic stirring bar (L 20 mm, Ø 10 mm) and
toluene (10 mL) were added to a roundꢀbottom flask to which a condenser was attached. The
temperature was cycled between 55 and 65 °C on a regular basis (5 min at 55 °C, 2 °C/min to 65
°C, 5 min at 65 °C, 1 °C/min to 55 °C), while the suspension was gently stirred. Samples were
taken after 5 min at 65 °C.
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Sampling:
For sampling, 100 µL of the suspension was taken using a syringe. The crystals were filtered off
on a P4 glass filter and air dried.
Sample analysis:
Analysis of the samples taken during the experiment was performed using chiral HPLC, which
gave good separation, but not the absolute configuration of the two peaks in the chromatogram.
To determine the absolute configuration, XꢀRay diffraction was used to elucidate the structure of
a single crystal. Designation of the HPLC peaks was done by sampling this single crystal, giving
only a single peak.
The ee of the samples was determined using chiral HPLC (ADH column, 20% IPA in heptane,
flow 1 mL minꢀ1, retention times: (Sa)ꢀ4 11.7 min, (Ra)ꢀ4 25.0 min).
AUTHOR INFORMATION
Corresponding Author
Hugo Meekes: H.Meekes@science.ru.nl
Author Contributions
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A.H.J.E., H.M., F.P.J.T.R. and E.V. designed the experiments and analyzed the data. A.H.J.E.,
P.v.S and H.J. performed the experiments. A.H.J.E. wrote the manuscript with contributions
from all other authors. All authors contributed to the discussions.
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Anthonius H. J. Engwerda, Pim van Schayik, Henjo Jagtenberg, Hugo Meekes, Floris P. J. T.
Rutjes and Elias Vlieg
Synopsis:
Atropisomers are chiral rotamers that possess an axis of chirality. By applying temperature
cycling or Viedma ripening, one such atropisomer could successfully be deracemized.
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