Large nonlinear effect observed in the enantiomeric excess of proline in solution and that in the solid state

Article abstract of DOI:10.1002/anie.200601506

(Chemical Equation Presented) A clue to the origin of chirality? A solution of proline with high enantiomeric excess (85-99% ee) was obtained from solid proline of only 10% ee through novel dissolution and crystallization processes (see scheme). This observation may be an explanation for the origin of chirality on Earth.

Full text of DOI:10.1002/anie.200601506

Angewandte
Chemie
Enantiomeric Enrichment
DOI: 10.1002/anie.200601506
Large Nonlinear Effect Observed in the Enantio-
meric Excess of Proline in Solution and That in
the Solid State**
Yujiro Hayashi,* Masayoshi Matsuzawa,
Junichiro Yamaguchi, Sayaka Yonehara,
Yasunobu Matsumoto, Mitsuru Shoji,
Daisuke Hashizume, and Hiroyuki Koshino
How homochiral amino acids and sugars arose out of a
presumably prochiral prebiotic environment is a puzzling
question,[1] to which many answers have been proposed: for
example, absolute asymmetric synthesis with circularly polar-
ized light, photoreactions in chiral crystals, and asymmetric
automultiplication with asymmetric autocatalysis, as exem-
[2]
plified by the recent workof Soai et al. There are reports
describing a connection between the chirality of amino acids
and sugars: Amplification of ee was observed in the a-
aminoxylation of an aldehyde using proline as catalyst to
generate a key intermediate of sugars,[3] while amino acids
[*] Prof. Dr. Y. Hayashi, M. Matsuzawa, J. Yamaguchi, S. Yonehara,
Y. Matsumoto, Dr. M. Shoji
Department of Industrial Chemistry
Faculty of Engineering
Tokyo University of Science
Kagurazaka, Shinjuku-ku, Tokyo 162-8601 (Japan)
Fax: (+81)3-5261-4631
E-mail: hayashi@ci.kagu.tus.ac.jp
Dr. D. Hashizume, Dr. H. Koshino
RIKEN
2-1 Hirosawa, Wako, Saitama 351-0198 (Japan)
[**] This work was partially supported by Toray Science Foundation and
a Grant-in-Aid for Scientific Research on Priority Areas 16073219
from MEXT. We thank Professors K. Soai (Tokyo University of
Science) and K. Saigo (The University of Tokyo) for helpful
discussions.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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have been proposed as asymmetric catalysts for the synthesis
of sugars.[4] Recently, Cordova et al. demonstrated the syn-
thesis of a hexose (55% ee) from proline with low ee
(20% ee), with a nonlinear effect.[5] Herein, we demonstrate
experimentally a connection between an amino acid with low
ee (10% ee) and a chiral sugar intermediate of high enantio-
meric purity (96% ee).
Amino acids promote several organic transformations,
and proline, a widely distributed amino acid, is one of the
most effective organic catalysts.[6] In 1971, Hajos and Parrish,
as well as Eder et al., reported an intramolecular aldol
reaction catalyzed by proline.[7] Following the observation of
the intermolecular version of this reaction by List, Lerner,
and Barbas in 2000,[8] other highly enantioselective catalytic
reactions using proline have been developed, including
aldol[9] and Mannich[10] reactions, and a-amination[11] and a-
aminoxylation[12] of carbonyl compounds.
We have observed that a solution of proline with high ee
can be obtained from solid proline of low optical purity during
the dissolution process. As proline is only very sparingly
soluble in pure CHCl3, and as the addition of EtOH increases
its solubility therein, we employed CHCl3 containing 1%
EtOH as solvent. CHCl3 stabilized with amylene (not with
EtOH) was distilled from CaH2 before use, and then EtOH
was added (1%). At first, reproducibility of the solubility was
poor. After several experiments, both the surface and the
particle size of the solid proline were found to be important.
Proline that had been recrystallized from EtOH and ground
with a mortar under an Ar atmosphere was employed.
The experiment using 10% ee l-rich proline was per-
formed as follows: CHCl3 (20 mL) containing 1% EtOH was
added to a mixture of l-proline (550 mg) and d-proline
(450 mg; 10% ee combined) at 08C, and the suspension was
stirred for 24 h at this temperature under an Ar atmosphere.
After filtration of the insoluble proline, a solution (17–19 mL)
containing proline (40–65 mg) was obtained, the ee value of
which was very high (85–99% ee). It is particularly unusual
that a proline solution with very high ee was obtained from
proline of low ee; this phenomenon is not observed in other
solvents such as EtOH and dimethyl sulfoxide.
Figure 1. Hydrogen-bonded dimer structure formed between the col-
umns in a crystal of l-proline.[13]
Figure 2. Hydrogen-bonded dimer structure formed between the col-
umns in a crystal of dl-proline.
crystals have very similar structural motifs, forming a column
À
A solution of proline with very high ee (97–99% ee) was
also obtained from proline with even lower ee (1.0% ee).
Even by using nearly racemic proline (< 0.4% ee), which was
prepared from l-proline (250 Æ 1 mg) and d-proline (250 Æ
1 mg), the optical purity of proline in solution was found to be
very high. With the exception of phenylalanine (Phe), we
were unable to demonstrate any enrichment of ee in CHCl3
solution with other amino acids (Val, Met, and Tyr) because of
their extremely low solubility in that solvent. In the case of
Phe, although it is only very sparingly soluble in CHCl3, a
solution of Phe with 10% ee was obtained from a solid of
40% ee. This observation also indicates that there is some-
thing special in the dissolution of proline.
To clarify the reason for these phenomena, the crystal
structures of l-proline[13] and dl-proline,[14] recrystallized
from EtOH, were analyzed (Figure 1, Figure 2). The powder
X-ray diffraction (XRD) method was used to confirm that the
crystal forms of the powdered l- and dl-prolines were the
same as those of the corresponding single crystals. Both
structure with N H···O hydrogen bonds. However, the joining
modes of these columns are quite different: In the chiral
crystal, the columns align antiparallel and each molecule in
the column connects with those in two neighboring columns
through hydrogen bonds to form a 2D sheet structure
(Figure 3). On the other hand, in the racemic crystal each
molecule in the column forms two centrosymmetric hydrogen
bonds with the nearest neighboring enantiomeric column to
form a ladder structure (Figure 4). These ladders are linked
À
by rather weakC H···O interactions. As the heterochiral
molecules bind together with two hydrogen bonds, their
association is energetically preferable to that of homochiral
molecules, and this causes racemic crystals to be much less
soluble than those of the pure enantiomers (0.01–0.09 gLÀ1
versus 6.1–6.3 gLÀ1 at 08C in CHCl3 containing 1% EtOH).
Therefore, crystals of dl-proline precipitate preferably from a
mixture of enantiomers in solution.
To shed more light on the reaction mechanism, the
following experiments were performed: 1) CHCl3 (100 mL)
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XRD (the results are summarized in Table 1 and Table 2,
respectively). Both experiments show an increase in dl-
proline content of the solid with reaction time. After 12 h,
Table 1: The effect of time on the ee of proline in solution and on the
content of the dl isomer in the solid.[a]
Entry
t [h]
Solubility
ee [%][c]
Content
[%][d]
[mgmLÀ1 [b]
]
1
2
3
4
0.17
1
6
2.9
0.3
1.3
3.5
7[e]
57[e]
96[e]
95[e]
7
46
77
84
12
[a] CHCl3 containing 1% EtOH was added to a mixture of l- and d-
proline; see text for details. [b] Solubility of proline in CHCl3/EtOH
(100:1). [c] ee of proline in solution. [d] Content of dl-proline in solid.
[e] d-enantiomer rich.
Table 2: The effect of time on the ee of proline in solution and on the
content of the dl isomer in the solid.[a]
Entry
t [h]
Solubility
ee [%][c]
Content
[%][d]
[mgmLÀ1 [b]
]
Figure 3. Crystal structure of l-proline.[13] O red, N blue, C black
(large), H black (small).
1
2
3
4
5
0
0.17
1
6
12
6.7
3.9
0.65
2.6
3.7
À100[e]
76[f]
0
33
54
83
92
68[f]
90[f]
92[f]
[a] d-proline was added to a suspension of l-proline in CHCl3 containing
1% EtOH; see text for details. [b] Solubility of proline in CHCl3/EtOH
(100:1). [c] ee of proline in solution. [d] Content of dl-proline in solid.
[e] l-enantiomer rich. [f] d-enantiomer rich.
most of the l- and d-proline had been converted into dl-
proline and the ee of proline in solution was very high
(> 90% ee). In the second experiment, the proline isomer in
excess in solution changed from the l to the d enantiomer
within 1 h, with the formation of solid dl-proline. Thus, the
highly selective dissolution of one enantiomer of proline is
caused not by a simple extraction of the excess enantiomer
but by the following dissolution and crystallization mecha-
nism: Soluble l- and d-prolines dissolve in the solvent, and
the less-soluble racemic dl-proline, but not a conglomerate,
precipitates.
The dissolution and crystallization process is also different
from that of standard recrystallization. Although the recrys-
tallization of proline from EtOH or from EtOH/Et2O[15] has
been known for a long time, there are no reports describing a
change in the ee value of proline by recrystallization, either in
solution or in the solid state. We thus examined the
recrystallization of proline (10% ee) in different solvents
and analyzed the ee of proline in the filtrate (Table 3). CHCl3
could not be used as solvent owing to the low solubility of
proline in this solvent alone. No increase in ee was observed in
H2O. Though a substantial increase in ee was observed in
EtOH or in iPrOH and water (1:1), it was not so large relative
to that observed with CHCl3 containing 1% EtOH.
Figure 4. Crystal structure of dl-proline. O red, N blue, C black (large),
H black (small).
and EtOH (1 mL) were added to a mixture of l-proline
(2.25 g) and d-proline (2.75 g; total 10% ee d-rich), and the
reaction mixture was stirred for a certain time. 2) d-proline
(2.75 g, total 10% ee d-rich) was added to a CHCl3/EtOH
suspension (100 mL:1 mL) of l-proline (2.25 g) at 08C, and
the reaction mixture was stirred for a certain time. In these
two reactions, the ee of proline in solution was measured
while the content of dl-proline in the solid was analyzed by
For some compounds, homochiral crystals have been
obtained from solutions of low ee by the preferential
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Table 3: The effect of solvent on the ee of proline in solution through
reaction of aldehydes with molecular oxygen under photo-
irradiation—plausible prebiotic conditions.[20] As an enantio-
merically enriched solution of proline might be separated
from solid proline by filtration through strata, one can
speculate that in the prebiotic era a similar mechanism
involving proline of very low ee was involved in the
generation of other biologically important homochiral
organic molecules.
recrystallization.[a]
Entry
Solvent
ee [%]
1
2
3
H2O
EtOH
iPrOH/H2O (1:1)
14
43
39
[a] Proline (10% ee) was recrystallized from the indicated solvent, and
the ee of proline in the filtrate was determined.
Some amino acids have been found in meteorites with
significant enantiomeric excess.[21] Though proline is scarcely
present in meteorites, it was found in the room-temperature
residue of an interstellar ice analogue that had been irradiated
with UV light under high vacuum at 12 K, which indicates
that proline may have been produced in the prebiotic era.[22]
Therefore, it seems possible that asymmetric photolysis in
interstellar clouds may produce optically active proline.
Under certain circumstances the imbalance thus generated
could be amplified into an optically enriched solution of
proline by selective dissolution. Such a solution can promote
many organic transformations and generate important inter-
mediates of sugar synthesis with very high optical purity, as
demonstrated in the present report. Though the present
reaction is only successful under certain limited conditions, it
may indicate a possible mechanism by which an amino acid of
low ee generated homochirality in biologically important
organic molecules in the prebiotic environment.[23]
crystallization of conglomerates,[16] a process that is distinct
from the present phenomena in which a solution with very
high ee is obtained from a solid of low ee. Though several
examples are known for which a chiral crystal is more soluble
than the corresponding racemic one, there is only one report
describing the enrichment of an enantiomer in solution during
recrystallization, a special case in which polymorphic trans-
formation occurs during crystallization.[17] In the present case,
a solution of proline with very high ee is obtained from a solid
of low ee during the processes of dissolution and crystalliza-
tion, a mechanism which is completely different to that of any
other known resolution.
As optically pure proline is known to promote several
asymmetric reactions, one possible application of the solution
of proline of high ee obtained from proline solid of low ee is a-
aminoxylation of propanal.[12a,b,c] As shown in Scheme 1, the
Received: November 28, 2004
Revised: May 9, 2006
Keywords: amino acids · asymmetric catalysis · carbohydrates ·
.
chirality · proline
Scheme 1. a-Aminoxylation of propanal using proline as catalyst. A
solution of proline prepared from solid proline (10% ee) used a) after
filtration gave the product with 96% ee and b) without filtration gave
the product with only 19% ee.
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product was obtained in 96% ee, demonstrating that this
proline solution can be applied to other useful asymmetric
transformations. When proline with 10% ee was employed in
a-aminoxylation without filtration, the ee of the product was
low (19% ee) and a slight nonlinear effect was observed, as
reported by Blackmond and co-workers.[3] This slight increase
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proline in solution is very high, but as the reaction proceeds
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generated product acts as a polarized solvent to bring both d-
and l-proline from the solid into the organic phase. That is,
while the ee of proline in the initial solution is extremely high,
this ee in solution decreases as the reaction progresses owing
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The fact that a solution of proline of high ee was obtained
from solid proline with low ee may be involved in the origin of
chirality on Earth. Proline has been used as the catalyst in a
short synthesis of sugars[4,5] and in the synthesis of a-
hydroxyaldehydes, key molecules for sugar synthesis, by
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