10.1002/anie.201808913
Angewandte Chemie International Edition
COMMUNICATION
with high affinity for only one of the two crystal forms may act as
a selective growth-inhibitor.[14] In practice, molecules that closely
enantiomer.[19] This results in a solid phase that already has a high
starting ee (around 25% after adding the racemization catalyst)
resemble one of the two enantiomers are selected for this purpose. when the Viedma ripening commences. The time required to
Importantly, the chiral additive should not alter its stereochemical
configuration during the experiment.
obtain a single enantiomer is therefore even shorter than already
achieved for the use of an additive only (starting from trans-2).
In this study, a combination of four enantiopure chiral additives
was synthesized,[15] all of which closely resemble the same
enantiomer of compound 2 (Figure 5). All additives contain three
chiral centers, of which one (carrying the hydroxyl group) cannot
epimerize under the influence of DBU. The locked chirality of this
stereocenter also ensures the desired chirality of the other two
centers (since epimerization of these centers would result in
sterically unfavored cis-orientations, see ESI). Using these tailor-
made additives, the outcome of the grinding experiments always
proceeded in the desired direction. The combination of the four
additives based on (R,R)-2 always resulted in (S,S)-2 as the
product, while (S,S)-based additives resulted in (R,R)-2. This
In conclusion, we have shown that the formation of one single out
of four stereoisomers using isomerization and subsequent
Viedma ripening is possible. The requirements are similar to those
for compounds with only a single stereocenter, but can in practice
be difficult. The desired pair of enantiomers should be the
thermodynamically most stable pair and should also crystallize as
a racemic conglomerate. However, when the most stable pair of
enantiomers crystallizes as a racemic compound, derivatization[20]
or salt formation[21] can additionally be used to convert it into a
conglomerate. Racemization can be more challenging, since
epimerization of all chiral centers should proceed under the same
conditions. These principles do not only hold for a molecule with
two, but also for more stereocenters. As long as these
requirements are met, Viedma ripening may be used for the
deracemization of any compound with multiple stereocenters.
phenomenon of opposing chirality has been extensively studied
16]
and is known as the Lahav rule of reversal.[13b,
Since a
combination of four additives was used in all experiments,[17] we
could not determine which of the four was most effective. The
deracemization curve shows a linear behavior, typical for the use
of chiral additives.[18] Not only could the desired enantiomer be
obtained using this approach, the time required for
deracemization was also significantly decreased (Figure 6). When
Acknowledgements
starting
from
the
racemic
trans-diastereomers,
the
deracemization time was reduced from 70 to 2.5 hours. When
starting from cis-2, the conversion time was even decreased to
less than one hour, in other words a reduction of almost a factor
100 was achieved.
Dr. Paul White is acknowledged for assistance with temperature-
dependent NMR experiments, dr. Dennis Löwik for help with CD
measurements and dr. Wester de Poel for taking some samples
of the grinding experiments.
Keywords: Chirality • Deracemization • Diastereomers • Viedma
Ripening • Racemization
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Figure 6: Curves showing the conversion of compound 2 into a single
enantiomer, using
5 mol% of the chiral additives 5a-d (ee stands for
enantiomeric excess; +100% ee implies only RR while –100% ee means only
SS). Experiments were either started from the racemic trans-(R,R/S,S) or cis-
(R,S/S,R) diastereomers. Within a minute after adding the racemization catalyst,
all experiments contained only the trans-diastereomer. When additives were
used, 5a-d were always used as a combination. Please note the two different
time scales on the x-axis.
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This increased conversion speed is induced in the initial phase of
the process. Fast epimerization of the cis-diastereomer results in
a supersaturated solution of the trans-enantiomers. Since the rate
of cis- to trans-epimerization is higher than that of racemization,
this results in crystallization of both trans-enantiomers in the
absence of an additive. In the presence of the additive, however,
crystallization of the enantiomer similar to the additive is
hampered, resulting in preferential crystallization of the other
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