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Kenso Soai et al.
Asymmetric autocatalysis triggered by triglycine sulfate withswitchable chirality by altering the direction of the applied
electric fieldOpen Access Article. Published on 13 May 2021. Downloaded on 10/20/2024 3:34:52 AM.
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Cite this: Chem. Commun., 2021,
57, 5999
Received 23rd April 2021,
Accepted 13th May 2021
DOI: 10.1039/d1cc02162a

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Asymmetric autocatalysis triggered by triglycine
sulfate with switchable chirality by altering thedirection of the applied electric field†
Tsuneomi Kawasaki, a Yoshiyasu Kaimori,a Seiya Shimada,a Natsuki Hara,aSusumu Sato,a Kenta Suzuki,a Toru Asahi,b Arimasa Matsumoto‡a andKenso Soai *ac

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Triglycine sulfate (TGS) acts as a chiral trigger for asymmetricautocatalysis with amplification of enantiomeric excess, i.e., theSoai reaction. Therefore, molecular chirality of highly enantioenriched organic compounds is controlled by a ferroelectric crystal
TGS, whose polarization is altered by an electric field.

Control of molecular chirality by the application of physical force
is one of the most challenging topics in science,1–3 and thisapproach can provide a new methodology for enantioselective
synthesis.4–7 The induction of chirality by physical force8 is an
important topic to consider with respect to the origin of biologicalhomochirality,9 which continues to attract tremendous attention
from scientists in many fields of research.10–12 An electromagnetic
force is often considered a possible inducer of molecular chirality
because electromagnetic waves can directly interact with organic
molecules. Actually, chiral electromagnetic force, circularly polarized light (CPL), can induce enantioselective decomposition13
and reactions14 of organic compounds, and asymmetric amplification during the crystallization15 or asymmetric autocatalysis16,17
can provide chiral organic products with a high enantiomeric
excess (ee) initiated by CPL irradiation. Furthermore, recent
observations have experimentally demonstrated that the combination of path direction of linearly polarized light and magnetic
field can provide chiral effects leading to the formation ofenantioenriched compounds.3,18 To our knowledge, there hasaDepartment of Applied Chemistry, Tokyo University of Science, Kagurazaka,
Shinjuku-ku, Tokyo, 162-8601, Japan. E-mail: soai@rs.kagu.tus.ac.jpbDepartment of Life Science and Medical Bioscience, Waseda University (TWIns),
Wakamatsu-cho, Shinjuku-ku, Tokyo, 162-8480, Japanc
Research Organization for Nano & Life Innovation, Waseda University,
Wasedatsurumaki-cho, Shinjuku-ku, Tokyo, 162-0041, Japan† Electronic supplementary information (ESI) available: Experimental methods,
crystallographic data, ortep drawings of P/M-triglycine sulfate and photo of
powdered TGS. CCDC 1993618 and 1993609. For ESI and crystallographic data
in CIF or other electronic format see DOI: 10.1039/d1cc02162a‡ Present address: Department of Chemistry, Biology and Environmental Science,
Nara Women’s University, Kita-Uoya Nishi-machi, Nara, 630-8506, Japan.

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been no apparent example of the control of molecular chirality
in enantioselective reaction by a ferroelectric crystal, whosechirality is induced by the application of a static electric field,
an achiral physical force.
Here, we describe the asymmetric autocatalysis of 5-pyrimidyl alkanol (the Soai reaction)12,16,19–24 initiated withferroelectric triglycine sulfate (TGS: (NH2CH2COOH)3H2SO4)
crystal, whose handedness is controlled by the application of astatic electric field (Fig. 1).
We first reported asymmetric autocatalysis with amplification of ee as a real chemical reaction.16 When diisopropylzinc(i-Pr2Zn) addition to pyrimidine-5-carbaldehyde 1 was performed in the presence of a catalytic amount of pyrimidyl
alkanol 2 with a very low ee (ca. 0.00005% ee), asymmetricautocatalysis could enhance the ee significantly to produce a
final product with very high ee (499.5% ee).25 Asymmetricautocatalysis, named as the Soai reaction,19,20 has enormous
power to recognize and amplify small chiral imbalances such ascarbon isotope chirality7 and crystal chirality;26,27 therefore,
asymmetric autocatalysis can connect the proposed origins ofchirality with enantiomerically enriched organic compounds.12
To induce molecular chirality using the controlled chirality of
TGS, asymmetric autocatalysis of 5-pyrimidyl alkanol 2(its isopropylzinc alkoxide 2 0 ) in the addition reaction ofi-Pr2Zn to pyrimidine-5-carbaldehyde 1 was performed withTGS operating as a chiral trigger (Fig. 1b). We assumed that
this reaction would allow the crystal chirality of TGS to bediscriminated and aﬀord highly enantioenriched product withthe handedness corresponding to TGS.
TGS (Fig. 2a) is a well-known ferroelectric crystal.28 Crystalsof this compound exhibit spontaneous electric polarization andpolarities, which can be controlled by the application of an
external static electric field. Moreover, crystals of TGS havechirality even though the components including glycine andsulfate ions are achiral. However, chiral crystals of TGS haverarely been used as a chiral source for enantioselective reactions despite their wide application as a ferroelectric material.

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Fig. 1 Concept and scheme of the present work: (a) control of theabsolute molecular chirality by selecting the direction of the static
electric field applied to triglycine sulfate (TGS) and asymmetric autocatalysis with amplification of ee. (b) Asymmetric autocatalysis of 5pyrimidyl alkanol 2 induced by P- and M-TGS as a heterogeneouschiral trigger, leading to highly enantioenriched (R)- and (S)-alkanol 2,
respectively.

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TGS crystal belongs to the monoclinic P21 space group(a = 9.44 Å, b = 12.6 Å, c = 5.74 Å, b = 1101),29 which does nothave inversion or mirror symmetry (Fig. 2b and Fig. S1, S2,
ESI†). There are three symmetrically independent glycine molecules in a unit cell. One glycine molecule (glycine II) exists inthe zwitterion form and has a large torsion angle of ca. +211
(P-conformation) or 211 (M-conformation) for the N–C–C–O
bond, whereas the other two glycine molecules (glycines I and
III) exist as almost planar structures in the protonated form.
The twisted glycine II induces crystal polarity because nosymmetry operator can invert or rotate the b-axis direction in
the P21 space group. Typically, TGS crystals that are grown froman aqueous solution are twinned crystals of both domains, inwhich spontaneous polarizations align parallelly or antiparallelly to the b-axis. The ferroelectricity is induced byexpanding and shrinking these twin domain areas in the crystal
in an electric field. The important point is that the symmetrical
relationship between these two domains is not a 1801 rotation
but a reflection.30 This means that the electric field application
also inverts the crystal chirality in addition to the polarity under
an electric field.
To examine the control of chirality of TGS, we preparedsingle crystals of TGS and undertook an absolute structure
determination by single-crystal X-ray diﬀraction analysis after
the application of an electric field. The naturally grown TGS
obtained from the slow evaporation of an aqueous solution of
sulfuric acid and glycine was elongated in the [010] direction
and had well-developed {101% } faces with characteristic {01% },{110} and {201% } faces (Fig. 2a). When the crystal is placed withthe (011% ) and (01% 1% ) faces up and triangle (201% ) face down
against the large front (101% ) surface, the polar b-axis was
directed and left in this axis setting. The crystal was sliced

Fig. 2 The chirality of TGS and its control by application of a static electric field. (a) Morphology of a single crystal of TGS [(NH2CH2COOH)3H2SO4].
(b) Comparison of the enantiomorphs of TGS at the molecular level and the twisted chiral structure of one glycine (glycine II) among three glycines in the
crystal lattice. (c) The absolute correlation between the direction of the applied electric field and the crystal chirality of the resulting TGS. (d) The controlof the chirality of TGS by switching the direction of the applied static electric field to one specific piece of TGS.

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perpendicular to the b-axis to give {010} surfaces (Fig. 2c). And astatic electric field was applied to this by attaching conductive
Cu tape on the {010} faces for poling the crystal. The chirality of
the resulting crystal was confirmed by anomalous dispersion
measurements in single-crystal X-ray diﬀraction analysis forseveral points of the crystal, which revealed that the absolute
crystal chirality of TGS was well-controlled by this method evenin the bulk size slice of the crystal (ca. 4 cm long and 5–7 mm
thick). When the electric field was applied antiparallel to theb-axis, the handedness of the resulting crystal was theM-conformation, and generation of the opposite Pconformation was observed when the electric field was applied
parallel to the b-axis. The Flack parameter with inversion twin
refinement is typically estimated to be around 0.1–0.2 with thestandard uncertainty around 0.1. The results mean that theglycine molecules predominantly twist in one direction andhave controlled chirality by the electric field (ca. 60–80%
crystal ee).
A mixture of pyrimidine-5-carbaldehyde 131,32 and TGS was
ground into a powder using a pestle and mortar, and theni-Pr2Zn was added dropwise. Furthermore, asymmetric autocatalysis by subsequent addition of aldehyde 1 and i-Pr2Zn tothe mixture gave highly enantioenriched 5-pyrimidyl alkanol 2
by the amplification of ee (Fig. 1b). When the reaction was
performed in the presence of M-TGS, obtained from the application of an electric field parallel to the b-axis, (S)-pyrimidyl
alkanol 2 was obtained with 65% ee (Table 1, series A, run 1). In
contrast, P-TGS was produced as a result of the application of astatic electric field from the direction antiparallel to the b-axis,
giving oppositely configured (R)-alkanol 2 with 68% ee after theamplification of the ee by asymmetric autocatalysis (run 2).
These results demonstrate that the direction of the static
electric field can be used to control the molecular chirality oforganic compounds through chiral ferroelectric TGS and asymmetric autocatalysis. It should be noted that P- and M-TGS usedin the experiments detailed in runs 1 and 2 were generated
from the one specific mother single crystal (crystal #1) by theapplication of oppositely directed static electric fields. The
sense of enantioselectivity between TGS and alkanol 2 was
reproducible, as shown in runs 3–6. Moreover, the ee of product2 could be enhanced to near enantiopure levels (499.5% ee) byconducting additional rounds of asymmetric autocatalysis, as
shown in runs 7 and 8.
It was also found that the chirality of the same piece of TGS
crystal is controlled repeatedly by applying the parallel andanti-parallel electric field successively (Fig. 2d and Table 1,series B). Thus, to confirm the stereochemical relationshipbetween the direction of the electric field and the molecularhandedness of the product of the asymmetric autocatalysis,
switching experiments with chiral TGS and its use as a chiraltrigger for asymmetric autocatalysis were conducted (Table 1,
runs 9–12). After the application of an electric field parallel tothe b-axis, half of the resulting P-crystal piece was used for theasymmetric autocatalysis affording (R)-product 2 with 92% ee(series B, run 9). The other piece was exposed to the electricfield directed in the opposite direction, leading to its

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Table 1 Asymmetric autocatalysis initiated with a TGS crystal after application of an electric field. Series A: M- and P-TGS submitted to theasymmetric autocatalysis were prepared by applying parallel and antiparallel electric fields to the sliced two pieces of TGS originating from one
specific single crystal, respectively (see also Fig. 2c). Series B: P- and MTGS submitted to the asymmetric autocatalysis were prepared by applying
parallel and anti-parallel electric fields successively to one specific sliced
piece of TGS (see also Fig. 2d)

TGS

Pyrimidyl alkanol 2

Single-crystal
Run batch

Direction of
Yield
E
Chirality (%)

Series A
1
#1
2
#1
3
#2
4
#2
5
#3
6
#3
7
#4

’
’
’
-

M
P
M
P
M
P
M

8

’

P

’
’ then ’’ then -

P
M
P
M

#4

Series B
9#5
10b #511 #6
12c #6ee (%)

Config.

73
65
62
68
41
43
50
40
69
76
74
39
67 (87)a 44(499.5)a80 (95)a 54(499.5)a

S
R
S
R
S
R
S

91
91
85
89

R
S
R
S

92
91
88
93

R

a

Additional rounds of asymmetric autocatalyses were performed toamplify the ee value significantly. b TGS crystal #5 was first applied withthe static electric field parallel to the b-axis of TGS. The resulting P-TGS
was used in run 9. The chirality of the same P-TGS crystal in run 9 was
switched to M by applying the static electric field of the opposite
direction of anti-parallel to the b-axis of TGS. c TGS crystal #6 wastreated in the same manner with the footnote b.

reconstruction as the opposite M-enantiomorph, which was
also used as a chiral trigger for asymmetric autocatalysis. As aresult, the enantioselectivity of the reaction was reversed toform the opposite (S)-alkanol 2 with a high 91% ee after
significant amplification of the ee by asymmetric autocatalysis(run 10). The results were reproducible, as shown in runs 11
and 12. Therefore, the switch of the direction of the electricfield is responsible for the change in the absolute configurationof the resulting product of asymmetric autocatalysis via
ferroelectric TGS.
In summary, we have demonstrated that ferroelectric TGS,
whose chirality is switchable by changing the direction of theapplied static electric field, can induce a highly enantioselective
synthesis through the significant amplification of ee by asymmetric autocatalysis of 5-pyrimidyl alkanol. The direction of anachiral static electric field and highly enantioenriched organic
products were successfully linked with each other via theferroelectric crystal of TGS; therefore, the present results provide new insight into the origin and amplification of biologicalhomochirality.
The authors thank Yuko Araki, Kunihiko Hatase and Koichi
Abe for the preliminary experiments. This work has been
financially supported by Grant-in-Aid for Scientific Researchfrom Japan Society for the Promotion of Science (JSPS
KAKENHI Grant Numbers 23685012, 26810026, 15H03781,
18H04518, 19K05482 and 19K22190, Grant-in-Aid for JSPS

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Research Fellow to Y. K. Number 15J03968) and by MEXTSupported Program for the Strategic Research Foundation atPrivate Universities, 2012–2016.

Conflicts of interest
There are no conflicts to declare.

Notes and references
1 B. L. Feringa and R. A. van Delden, Angew. Chem., Int. Ed., 1999, 38,
3418–3438.
2 K.-H. Ernst, Phys. Status Solidi, 2012, 249, 2057–2088.
3 G. L. Rikken and E. Raupach, Nature, 2000, 405, 932–935.
4 R. Naaman, Y. Paltiel and D. H. Waldeck, Nat. Rev. Chem., 2019, 3,
250–260.
5 J. D. Horvath and A. J. Gellman, J. Am. Chem. Soc., 2001, 123,
7953–7954.
6 J. M. Ribo, J. Crusats, F. Sagués, J. Claret and R. Rubires, Science,
2001, 292, 2063–2066.
7 T. Kawasaki, Y. Matsumura, T. Tsutsumi, K. Suzuki, M. Ito and
K. Soai, Science, 2009, 324, 492–495.
8 M. Avalos, R. Babiano, P. Cintas, J. L. Jimenez, J. C. Palacios andL. D. Barron, Chem. Rev., 1998, 98, 2391–2404.
9 M. Bolli, R. Micura and A. Eschenmoser, Chem. Biol., 1997, 4, 309–320.
10 I. Weissbuch and M. Lahav, Chem. Rev., 2011, 111, 3236–3267.
11 (a) D. K. Kondepudi and K. Asakura, Acc. Chem. Res., 2001, 34,
946–954; (b) C. Viedma, Phys. Rev. Lett., 2005, 94, 065504.
12 K. Soai, T. Kawasaki and A. Matsumoto, Acc. Chem. Res., 2014, 47,
3643–3654.
13 H. Nishino, A. Kosaka, G. A. Hembury, F. Aoki, K. Miyauchi,
H. Shitomi, H. Onuki and Y. Inoue, J. Am. Chem. Soc., 2002, 124,
11618–11627.
14 (a) H. Kagan, A. Moradpour, J. F. Nicoud, G. Balavoine and
G. Tsoucaris, J. Am. Chem. Soc., 1971, 93, 2353–2354;(b) W. J. Bernstein, M. Calvin and O. Buchardt, J. Am. Chem. Soc.,
1972, 94, 494–498.
15 W. L. Noorduin, A. C. Bode, M. van der Meijden, H. Meekes, A. F. van
Etteger, W. J. P. van Enckevort, P. C. M. Christianen, B. Kaptein,
R. M. Kellogg, T. Rasing and E. Vlieg, Nat. Chem., 2009, 1, 729–732.
16 K. Soai, T. Shibata, H. Morioka and K. Choji, Nature, 1995, 378, 767–768.
17 (a) T. Kawasaki, M. Sato, S. Ishiguro, T. Saito, Y. Morishita, I. Sato,
H. Nishino, Y. Inoue and K. Soai, J. Am. Chem. Soc., 2005, 127,
3274–3275; (b) I. Sato, R. Sugie, Y. Matsueda, Y. Furumura andK. Soai, Angew. Chem., Int. Ed., 2004, 43, 4490–4492.

6002 | Chem. Commun., 2021, 57, 5999–6002

ChemComm
18 Y. Kitagawa, H. Segawa and K. Ishii, Angew. Chem., Int. Ed., 2011, 50,
9133–9136.
19 (a) T. Gehring, M. Quaranta, B. Odell, D. G. Blackmond andJ. M. Brown, Angew. Chem., Int. Ed., 2012, 51, 9539–9542;(b) L. Schiaﬃno and G. Ercolani, Angew. Chem., Int. Ed., 2008, 47,
6832–6835.
20 K. Mislow, Collect. Czech. Chem. Commun., 2003, 68, 849–864.
21 K. Micskei, G. Rabai, E. Gal, L. Caglioti and G. Palyi, J. Phys. Chem. B,
2008, 112, 9196–9200.
22 (a) M. E. Noble-Teran, J.-M. Cruz, J.-C. Micheau and T. Buhse,
ChemCatChem, 2018, 10, 642–648; (b) M. Funes-Maldonado,
B. Sieng and M. Amedjkouh, Org. Lett., 2016, 18, 2536–2539;(c) I. D. Gridnev and A. K. Vorobiev, ACS Catal., 2012, 2,
2137–2149; (d) É. Dóka and G. Lente, J. Am. Chem. Soc., 2011, 133,
17878–17881.
23 (a) S. V. Athavale, A. Simon, K. N. Houk and S. E. Denmark, Nat.
Chem., 2020, 12, 412–423; (b) O. Trapp, S. Lamour, F. Maier,A. F. Siegle, K. Zawatzky and B. F. Straub, Chem. – Eur. J., 2020,
26, 15871–15880.
24 Reviews: (a) K. Soai, T. Kawasaki and A. Matsumoto, Symmetry, 2019,11, 694; (b) K. Soai, Proc. Jpn. Acad., Ser. B, 2019, 95, 89–109;(c) D. G. Blackmond, Chem. Rev., 2020, 120, 4831–4847;(d) T. Buhse, J. M. Cruz, M. E. Noble-Terán, D. Hochberg,
J. M. Ribó, J. Crusats and J.-C. Micheau, Chem. Rev., 2021, 121,
2147–2229.
25 I. Sato, H. Urabe, S. Ishiguro, T. Shibata and K. Soai, Angew. Chem.,
Int. Ed., 2003, 42, 315–317.
26 K. Soai, S. Osanai, K. Kadowaki, S. Yonekubo, T. Shibata and I. Sato,J. Am. Chem. Soc., 1999, 121, 11235–11236.
27 (a) T. Kawasaki, K. Jo, H. Igarashi, I. Sato, M. Nagano, H. Koshima
and K. Soai, Angew. Chem., Int. Ed., 2005, 44, 2774–2777;(b) H. Shindo, Y. Shirota, K. Niki, T. Kawasaki, K. Suzuki, Y. Araki,
A. Matsumoto and K. Soai, Angew. Chem., Int. Ed., 2013, 52,
9135–9138.
28 (a) B. T. Matthias, C. E. Miller and J. P. Remeika, Phys. Rev., 1956,
104, 849–850; (b) A. Lurio and E. Stern, J. Appl. Phys., 1960, 31,
1125–1126; (c) S. N. Drozhdin and O. M. Golitsyna, Phys. Solid State,
2012, 54, 905–910; (d) J. M. Hudspeth, D. J. Goossens, T. R. Welberry
and M. J. Gutmann, J. Mater. Sci., 2013, 48, 6605–6612.
29 (a) S. Hoshino, Y. Okaya and R. Pepinsky, Phys. Rev., 1959, 115,
323–330; (b) E. A. Wood and A. N. Holden, Acta Crystallogr., 1957, 10,
145–146.
30 J. Kobayashi, K. Uchino, H. Matsuyama and K. Saito, J. Appl. Phys.,
1991, 69, 409–413.
31 T. Shibata, S. Yonekubo and K. Soai, Angew. Chem., Int. Ed., 1999, 38,
659–661.
32 Y. Kaimori, Y. Hiyoshi, T. Kawasaki, A. Matsumoto and K. Soai,
Chem. Commun., 2019, 55, 5223–5226.

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