Attrition-enhanced deracemization of an amino acid derivative that forms an epitaxial racemic conglomerate

Article abstract of DOI:10.1002/anie.200802468

(Chemical Equation Presented) Just bead it! Despite the complication of enantiomeric epitaxial behavior, a derivative of phenylalanine was completely resolved (see picture). Racemization takes place by abrasively grinding crystals of the compound in a saturated solution. By studying the influence of different crystal sizes, it was found that Ostwald ripening plays an important role in this process. DBU = 1,8-diazabicyclo-[5.4.0]undec-7-ene.

Full text of DOI:10.1002/anie.200802468

Communications
DOI: 10.1002/anie.200802468
Chiral Resolution
Attrition-Enhanced Deracemization of an Amino Acid
Derivative That Forms an Epitaxial Racemic
Conglomerate**
Bernard Kaptein,* Wim L. Noorduin, Hugo Meekes, Willem J. P. van Enckevort,
Richard M. Kellogg,* and Elias Vlieg*
Angewandte
Chemie
7226
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 7226 –7229

Angewandte
Chemie
Unraveling the origins of single chirality as found in nature is
a fundamental scientific goal. Moreover, such understanding
has practical ramifications for the preparation of enantio-
merically pure compounds, including pharmaceutical compo-
nents. Separate R and S solid phases (known as racemic
conglomerates) were the starting point for obtaining enan-
tiomerically pure compounds from racemic mixtures when
Pasteur manually sorted the mirror-image crystals of a
tartrate salt.[1] In the direct resolution of conglomerates,
enantiomers of the desired handedness can be obtained more
efficiently by preferential crystallization through enantiose-
lective seeding or by using enantiomerically pure tailor-made
additives.[2–5] Although applied on an industrial scale nowa-
days, the yields in a single operation are limited and often this
type of resolution is hampered by mutual epitaxial growth of
the enantiomers.[6] In the latter case, enantioselective seeding
is of no use.
Scheme 1, was chosen as the starting material for attrition-
enhanced deracemization, as it crystallizes as a conglomer-
ate.[14] Owing to the presence of a relatively acidic hydrogen
atom at the a carbon atom of 1, this compound undergoes
ready racemization in solution under basic conditions
(pKa=19.0).[15]
Scheme 1. Synthesis of 1 from phenylalanine.
From this perspective, the recently reported attrition-
enhanced complete deracemization of NaClO3 and other
achiral salts is of interest, as it occurs under near-equilibrium
conditions.[7,8] On application of this abrasive grinding
technique to the solid phase of a nearly racemic nonproteo-
genic amino acid derivative in contact with a saturated
solution, in which racemization takes place, the solid phase
evolved smoothly to a single chiral end state.[9,10] An
explanation for this deracemization process was given in
terms of attrition-enhanced Ostwald ripening: the dissolution
of small crystals in favor of larger ones.[11–13] Herein, we
demonstrate for a conglomerate derivative of the natural
amino acid phenylalanine that attrition-enhanced total reso-
lution is possible for a system that exhibits the complication of
enantiomeric epitaxial growth. Furthermore, we provide
support for the role of Ostwald ripening in this process.
The compound N-(4-chlorobenzylidene)phenylalanine
methyl ester (1), which was synthesized as indicated in
X-ray crystal-structure determination of single crystals
grown from a solution of (S)-1 in isopropyl alcohol revealed
that this compound crystallizes in the space group P212121
(Figure 1; see the Supporting Information). The presence of
Figure 1. Crystal structure of (S)-1 viewed along the a axis.
the relatively heavy chloride atom enabled the assignment of
the S absolute configuration by anomalous dispersion.[16]
Crystals grown from both racemic and enantiomerically
pure solutions of 1 were analyzed by X-ray powder diffrac-
tion. The two patterns were identical and showed good
resemblance to those calculated from the single-crystal
structure. However, the analysis by HPLC on a chiral phase
of individual crystals grown from the racemic solution
revealed these crystals to be almost racemic. This result is
inconsistent with expectations for a conglomerate.[17]
[*] Dr. B. Kaptein
Innovative Synthesis & Catalysis, DSM Pharmaceutical Products
PO Box 18, 6160 MD Geleen (The Netherlands)
Fax: (+31)46-476-7604
E-mail: bernard.kaptein@dsm.com
Prof. Dr. R. M. Kellogg
Syncom BV, Kadijk 3, 9747 AT Groningen (The Netherlands)
Fax: (+31)50-575-399
E-mail: r.m.kellogg@syncom.nl
W. L. Noorduin, Dr. H. Meekes, Dr. W. J. P. van Enckevort,
Prof. Dr. E. Vlieg
We investigated this paradoxical situation further by
partial dissolution of the crystals grown from the racemic
mixture in a saturated enantiomerically pure solution.[6j,18]
The enantioselective dissolution of fragments of the crystal
was observed by optical microscopy (Figure 2), which indi-
cated that the crystals are composed of domains of single
chirality. A crystal that consists of many domains of chirality,
both left- and right-handed, will thus be nearly racemic.
By polarization microscopy and X-ray diffraction, we
found that these domains were all well ordered as match-
shaped crystallites stacked parallel to the crystallographic
[100] direction. The morphology of the resulting mutual
epitaxial conglomerate is made up of {100} top faces and {011}
IMM Solid State Chemistry, Radboud University Nijmegen
Heyendaalseweg 135, 6525 AJ Nijmegen (The Netherlands)
Fax: (+31)24-365-3067
E-mail: e.vlieg@science.ru.nl
[**] J. M. M. Smits is acknowledged for performing the X-ray single-
crystal structure determination. The SNN agency (Cooperation
Northern Netherlands)and the European Fund for Regional
Development (EFRO)are acknowledged for partial financial support
of this research.
Supporting information for this article, including experimental
details of the synthesis, X-ray crystal-structure analysis, and
deracemization of 1, are given in the supporting information is
available on the WWW under http://dx.doi.org/10.1002/anie.
200802468.
Angew. Chem. Int. Ed. 2008, 47, 7226 –7229
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7227

Communications
Figure 3. Typical change in the enantiomeric composition of the solid
phase during grinding (left; (R)-1: red bars, (S)-1: blue bars); this
evolution corresponds to an exponential increase in the enantiomeric
excess of (R)-1 (right). The initial ee value in the solid phase before
dissolution is 0.35%; the ee value increases slightly upon dissolution.
Figure 2. Left: Optical microscopy images showing the partial dissolu-
tion of (RS)-1 in a saturated solution of (S)-1 in isopropyl alcohol
(time interval between images: 10 min). Right: Schematic representa-
tion of the enantioselective dissolution; the enantiomorphs of (R)- and
(S)-1 are colored red and blue, respectively.
racemic 1 of approximately 20 wt% results in a relatively high
deracemization rate.[10]
To obtain more insight into the role of Ostwald ripening in
the deracemization process, we studied the effect of the initial
crystal-size distribution on deracemization. Two enantiomer-
ically pure solution–solid mixtures were prepared and sub-
jected to racemizing conditions. One mixture was ground by
glass beads to give many small crystals, whereas the other
mixture, which contained the opposite enantiomer, was
stirred only gently in the absence of glass beads, so that the
crystals remained relatively large. The latter mixture was
added to the former, and deracemization was monitored with
respect to time. Even mixtures with an initial excess of the
enantiomer present as small crystals evolved rapidly to a
single chiral solid phase of the enantiomer initially present as
large crystals (Figure 4; see the Supporting Information for
deracemization to give the opposite enantiomer). These
results clearly demonstrate the Ostwald ripening character
of this process, whereby large crystals grow at the expense of
smaller crystals.
side faces in terms of the crystallographic axes of the
individual domains. As the enantiomers crystallize epitaxially
on one another, standard resolution by preferential crystal-
lization is not possible.
Intrigued by this challenge, we tried to deracemize these
epitaxial conglomerate crystals to give a single chiral solid
phase by using the recently developed method of attrition-
enhanced Ostwald ripening (Scheme 2).[7,9,10] For these near-
equilibrium deracemization experiments, nearly racemic
Scheme 2. Chemical and physical equilibria in the process of attrition-
enhanced crystallization/dissolution of 1. DBU=1,8-diazabicyclo-
[5.4.0]undec-7-ene.
mixtures of 1 (3.2 g) were suspended in MeOH (10.0 g) and
ground by magnetic stirring (600 rpm) in the presence of glass
beads (6.0 g) at ambient temperature. Once the equilibrium
between the solution and solid states had been established,
the racemization in solution was initiated by the addition of
the base DBU (10 mol% with respect to 1).[19] Samples of the
solid were collected over time, and the ee value was measured
by HPLC. We found that even a slight initial enantiomeric
imbalance of 0.35% ee in 1 was sufficient to direct deracem-
ization within 4–5 days to provide the enantiomer initially in
excess in enantiomerically pure form in the solid state
(Figure 3; see the Supporting Information for the opposite
enantiomer). The evolution of the ee value of 1 in the solid
state with time follows the exponential behavior typical for
this process (Figure 3, right), despite the epitaxial behav-
ior.[10,13] Although the rate of racemization of 1 in the solution
phase is relatively low (t1/2 ꢀ 8 min), the high solubility of
Figure 4. Evolution of the solid-phase enantiomeric ratio of 1, initially
composed of an abundance of small crystals of (R)-1 and a minor
population of large crystals of (S)-1. The small crystals dissolve rapidly
and nurture the larger (S)-1 crystals until complete deracemization has
occurred.
The crystal packing of 1 is mainly determined by weak van
der Waals and dipole forces, as the molecule is not able to
form any hydrogen bonds. These rather isotropic weak forces
should make the crystallization process sensitive to epitaxial
2D nucleation of the opposite enantiomer. Gervais et al.
explained the alternating formation of the two chiral domains
by oscillating local supersaturation in the solution.[6j] During
the growth of one specific domain, the supersaturation of the
corresponding enantiomer decreases, and, therefore, the
7228
www.angewandte.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2008, 47, 7226 –7229

Angewandte
Chemie
Engl. 1996, 35, 1666; f) M. Berfeld, D. Zbaida, L. Leiserowitz, M.
nucleation of the other enantiomer becomes more likely.
Once that domain starts growing, this process repeats itself.
The local differences in supersaturation that cause this
alternating 2D nucleation could be circumvented by gentle
stirring of the mixture to give crystals with a significant
enantiomeric excess.[6j] Although in our near-equilibrium
experiments primary nucleation is a rare and probably
negligible process, epitaxial heterochiral nucleation, albeit
slow, can not be excluded. Vigorous stirring and solution-
phase racemization, however, remove local differences in
supersaturation between the two enantiomers.[20,21] Addition-
ally, the continued fragmentation of the crystals is more likely
to occur at the domain boundaries and thus separate the
enantiomorphous phases.
Lahav, Adv. Mater. 1999, 11, 328; g) D. Zbiada, M. Lahav, K.
Drauz, G. Knaup, M. Kottenhahn, Tetrahedron 2000, 56, 6645;
h) R. G. Kostyanovsky, K. A. Lyssenko, A. N. Kravchenko, O. V.
Lebedev, G. K. Kadorkina, V. R. Kostyanovsky, Mendeleev
Commun. 2001, 11, 134; i) S. Beilles, P. Cardinael, E. Ndziꢀ, S.
Petit, G. Coquerel, Chem. Eng. Sci. 2001, 56, 2281; j) C. Gervais,
S. Beilles, P. Cardinael, S. Petit, G. Coquerel,J. Phys. Chem. B
2002, 106, 646; k) V. Yu. Torbeev, K. A. Lyssenko, O. N.
Kharybin, M. Yu. Antipin, R. G. Kostyanovsky, J. Phys. Chem.
B 2003, 107, 13523; l) P. A. Levkin, V. Yu. Torbeev, D. A. Lenev,
R. G. Kostyanovsky Top. Stereochem. 2006, 25, 81; m) J. Th. H.
van Eupen, W. W. J. Elffrink, R. Keltjens, P. Bennema, R.
de Gelder, J. M. M. Smits, E. R. H. van Eck, A. P. M. Kentgens,
M. A. Deij, H. Meekes, E. Vlieg, Cryst. GrowthDes. 2008, 8, 71.
[7] C. Viedma, Phys. Rev. Lett. 2005, 94, 065504.
[8] P. S. M. Cheung, J. Gagnon, J. Surprenant, Y. Tao, H. Xu, L. A.
Cuccia, Chem. Commun. 2008, 987.
The mutual epitaxial growth of enantiomers in conglom-
erate crystals has been reported frequently.[6] Herein, we have
described the use of attrition-enhanced deracemization to
resolve the solid phase in liquid–solid mixtures of 1. Under
near-equilibrium conditions, a mixture of enantiomers in the
form of epitaxial racemic conglomerate crystals was con-
verted completely into a single chiral solid phase of the
desired handedness. The observation that a population of
small crystals, initially in enantiomeric excess, nurtures the
population of large crystals of the opposite handedness
supports the fundamental role of Ostwald ripening in this
process. In conclusion, this method of attrition-enhanced
Ostwald ripening offers an attractive alternative in situations
in which the formation of epitaxial racemic conglomerates
hampers resolution by preferential crystallization.
[9] W. L. Noorduin, T. Izumi, A. Millemaggi, M. Leeman, H.
Meekes, W. J. P. van Enckevort, R. M. Kellogg, B. Kaptein, E.
Vlieg, D. G. Blackmond, J. Am. Chem. Soc. 2008, 130, 1158.
[10] W. L. Noorduin, H. Meekes, W. J. P. van Enckevort, A. Mille-
maggi, M. Leeman, B. Kaptein, R. M. Kellogg, E. Vlieg, Angew.
Chem. 2008, DOI: 10.1002/anie.200801846; Angew. Chem. Int.
Ed. 2008, DOI: 10.1002/ange.200801846.
[11] C. Viedma, Astrobiology 2007, 7, 312.
[12] J. H. E. Cartwright, O. Piro, I. Tuval, Phys. Rev. Lett. 2007, 98,
165501.
[13] W. L. Noorduin, H. Meekes, A. A. C. Bode, W. J. P. van Enck-
evort, B. Kaptein, R. M. Kellogg, E. Vlieg, Cryst. GrowthDes.
2008, 8, 1675.
[14] Y. Takahashi, K. Arai, Y. Obara, H. Matsumoto (Nissan Chem.
Industr., Ltd. Japan, 1986), JP61103852 ( Chem. Abstr. 1986, 105,
43327).
[15] K. Maruoka, T. Ooi, Chem. Rev. 2003, 103, 3013.
[16] J. M. Bijvoet, A. F. Peerdeman, A. J. van Bommel, Nature 1951,
168, 271.
Received: May 27, 2008
Published online: August 11, 2008
[17] Similar observations were made for crystals grown from MeOH.
[18] K. Toyokura, K. Mizukawa, M. Kurotani in CGOM3, ACS
Conference Proceedings Series (Eds.: A. S. Myerson, D. A.
Green, P. Meenan), Washington DC, 1996, 72.
[19] It is essential to use new glassware, beads, and stirring bars for
each experiment to avoid chiral contamination; see also ref. [9]
and: a) D. W. Armstrong, J. P. Kullman, X. Chen, M. Rowe,
Chirality 2001, 13, 153; b) M. Lahav, I. Weissbuch, E. Shavit, C.
Reiner, G. J. Nicholson, V. Schurig, Origin Life Evol. Biosph.
2006, 36, 151; c) C. Viedma, Cryst. GrowthDes. 2007, 7, 553; d) S.
Osuna-Esteban, M.-P. Zorzano, C. Menor-Salvꢁn, M. Ruiz-
Bermejo, S. Veintemillas-Verdaguer, Phys. Rev. Lett. 2008, 100,
146102.
Keywords: amino acids · chiral resolution · epitaxial growth ·
grinding · Ostwald ripening
.
[1] L. Pasteur, C. R. Hebd. Seance Acad. Sci. Paris 1848, 26, 535.
[2] J. Jacques, A. Collet, S. H. Wilen, Enantiomers, Racemates and
Resolution, Krieger, Malabar, 1994.
[3] L. Addadi, Z. Berkovitch-Yellin, N. Domb, E. Gati, M. Lahav, L.
Leiserowitz, Nature 1982, 296, 21.
[4] L. Addadi, S. Weinstein, E. Gati, I. Weissbuch, M. Lahav, J. Am.
Chem. Soc. 1982, 104, 4610.
[5] G. Coquerel, Top. Curr. Chem. 2007, 269, 1.
[20] This effect might explain the successful crystallization-induced
enantiomeric transformation of 1 and of 1-(4-chlorophenyl)-4,4-
dimethyl-2-(lH-1,2,4-triazol-l-yl)pentan-3-one from solution. In
the absence of solution-phase racemization, these compounds
form epitaxial racemic conglomerates.[14,6d,21]
[6] a) S. Furberg, O. Hassel, Acta Chem. Scand. 1950, 4, 1020;
b) B. S. Green, M. Knossow, Science 1981, 214, 795; c) I.
Weissbuch, D. Zbaida, L. Addadi, L. Leiserowith, M. Lahav, J.
Am. Chem. Soc. 1987, 109, 1869; d) R. J. Davey, S. N. Black, L. J.
Williams, D. M. McEwan, D. E. Sadler, J. Cryst. Growth 1990,
102, 97; e) G. A. Potter, C. Garcia, R. McCagau, B. Adger, A.
Collet, Angew. Chem. 1996, 108, 1780; Angew. Chem. Int. Ed.
[21] S. N. Black, L. J. Williams, R. J. Davey, F. Moffatt, R. V. H. Jones,
D. M. McEwan, D. E. Sadler, Tetrahedron 1989, 45, 2677.
Angew. Chem. Int. Ed. 2008, 47, 7226 –7229
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org 7229