Spontaneous Symmetry Breaking in the Formation of Supramolecular Polymers: Implications for the Origin of Biological Homochirality

Article abstract of DOI:10.1002/anie.201812808

Aqueous solutions of the achiral, monomeric, nucleobase mimics (2,4,6-triaminopyrimidine, TAP, and a cyanuric acid derivative, CyCo6) spontaneously assemble into macroscopic homochiral domains of supramolecular polymers. These assemblies exhibit a high degree of chiral amplification. Addition of a small quantity of one handedness of a chiral derivative of CyCo6 generates exclusively homochiral structures. This system exhibits the highest reported degree of chiral amplification for dynamic helical polymers or supramolecular helices. Significantly, homochiral polymers comprised of hexameric rosettes with structural features that resemble nucleic acids are formed from mixtures of cyanuric acid (Cy) and ribonucleotides (l-, d-pTARC) that arise spontaneously from the reaction of TAP with the sugars. These findings support the hypothesis that nucleic acid homochirality was a result of symmetry breaking at the supramolecular polymer level.

Full text of DOI:10.1002/anie.201812808

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
www.angewandte.org
Accepted Article
Title: Spontaneous Symmetry Breaking in the Formation of
Supramolecular Polymers: Implications for the Origin of Biological
Homochirality
Authors: Nicholas V. Hud, Gary Schuster, Suneesh Karunakaran, Brian
Cafferty, and Angela Weigert-Muñoz
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201812808
Angew. Chem. 10.1002/ange.201812808
Link to VoR: http://dx.doi.org/10.1002/anie.201812808
http://dx.doi.org/10.1002/ange.201812808

10.1002/anie.201812808
Angewandte Chemie International Edition
COMMUNICATION
Spontaneous Symmetry Breaking in the Formation of
Supramolecular Polymers: Implications for the Origin of
Biological Homochirality
Suneesh C. Karunakaran, Brian J. Cafferty, Angela Weigert-Muñoz, Gary B. Schuster and
Nicholas V. Hud*
Abstract: Aqueous solutions of the achiral, monomeric, nucleobase
mimics triaminopyrimidine (TAP) and a cyanuric acid derivative
(CyCo6) spontaneously assemble into macroscopic homochiral
domains of supramolecular polymers. These assemblies exhibit a
high degree of chiral amplification. Addition of a small quantity of one
handedness of a chiral derivative of CyCo6 generates exclusively
homochiral structures. This system exhibits the highest reported
degree of chiral amplification for dynamic helical polymers or
supramolecular helices. Significantly, homochiral polymers comprised
of hexameric rosettes with structural features that resemble nucleic
acids are formed from mixtures of cyanuric acid (Cy) and
ribonucleotides (L-, D-pTARC) that arise spontaneously from the
reaction of TAP with the sugars. These findings support the
hypothesis that nucleic acid homochirality was a result of symmetry
breaking at the supramolecular polymer level.
spontaneous symmetry breaking for a simple, achiral, hydrogen-
bonded N-heterocycle.[1b] They recognized the significance of this
finding and speculated that the development of homochirality in
biological systems could have occurred in similar heterocycles
connected to ribose phosphate units. Here, we report the
discovery that spontaneously formed ribose-5-phosphate
substituted N-heterocycles[9] self-assemble in aqueous solution to
form macroscopic domains of homochiral structures. This finding
may provide a clue to the origin of homochirality in living systems.
Our lab has shown that the nucleobase analogs 2,4,6-
triaminopyrimidine (TAP) and a cyanuric acid (Cy) modified with
a hexanoic acid “tail” (CyCo6) associate by hydrogen bonding in
aqueous solution to form hexameric rosettes (Figure 1a).[10]
Hydrophobic interactions drive the stacking of these rosettes into
micron-length fibers that form hydrogels.[11] While examining
these gels, we were surprised to discover that they exhibit strong
circular dichroism (CD) signals (Figure 1b), even though they are
comprised exclusively of achiral components. The CD spectrum
of the gel is temperature dependent; it disappears around 40 °C
and reappears on cooling, sometimes with the opposite sign, and
becomes more intense as the sample temperature is lowered
(Figure 1b). There are corresponding temperature dependent
changes to the absorption spectrum of the gel (Figure S1, see the
Supporting Information). Independently prepared gel samples
have variable CD signs, intensity, and fine structure (Figure 1c).
For example, examination of forty samples by CD revealed
positive values nineteen times and negative values twenty-one
times for the band at 280 nm.
Although homochirality is an essential condition of living systems,
its origin from achiral and racemic (or nearly racemic) precursors
is an enduring puzzle.[1] It is well known that a small amount of a
chiral additive or a small enantiomeric excess of a chiral
constituent can control the orientation of an entire assembly of
chiral or achiral components.[2] In one manifestation, named
“Sergeants and Soldiers” by Green,[3] the helicity of an assembly
of achiral units is induced and controlled by a small amount of a
chiral additive. In a second case, Green’s “Majority Rules”, [4] an
extreme nonlinear amplification of a small enantiomeric excess
causes a large assembly to adopt a single helicity. Either of these
phenomena operating in a primordial pool could have induced
localized homochirality in a molecular assembly.
These observations indicate that this system spontaneously
forms temperature sensitive, reversible supramolecular polymers
Less widely studied is the spontaneous symmetry breaking
in some isotropic solutions of achiral compounds by chirality
discrimination or synchronization that yields domains where one
handedness dominates.[5] An analogous phenomenon exists in
crystallology where conglomerates form that are composed of
individual crystals of one handedness but in which the entire
ensemble of crystals is racemic.[6] The vast majority of
spontaneously resolving systems are found to occur in organic
solvents where weak solvation energy is overcome by long-range
intermolecular forces,[7] although there are examples of such
phenomena in alcohol.[8] A recent breakthrough in this field
occurred when Janietz, Tschierske and co-workers reported
with helical domains that have
a uniform or dominant
handedness.[12] The observed variation in CD band intensity and
sign suggested that there are overlapping domains of the two
handednesses within the ca.
8
mm diameter of the
spectropolarimeter’s light beam. This explanation was confirmed
by analyses of thin gel samples with a custom-built two-
dimensional (2D) CD scanner having a 0.8 mm beam diameter
(see the Supporting Information for instrumental details), which
revealed a patchwork of macroscopic (1-20 mm) domains whose
spectra varied in intensity and sign (Figure 2a). The CD spectra
associated with individual pixels are shown in Figure S2 (see the
Supporting Information). Similar experiments using the same
strain-free quartz plates resulted in different domain patterns (see
the Supporting Information, Figure S3).
The formation of chiral superhelical structures (i.e., twisted
bundles of hexad stacks)[13] within domains of the TAP-CyCo6
gels was confirmed by scanning electron microscopy (SEM).
These helical fiber bundles were observed to have opposite
handedness in different domains within the same sample (Figure
[*]
Dr. S. C. Karaunakaran, Dr. B. J. Cafferty, Ms. A. Weigert-Muñoz,
Prof. Dr. G. B. Schuster, Prof. Dr. N. V. Hud, School of Chemistry
and Biochemistry, Parker H. Petit Institute for Bioengineering and
Bioscience Georgia Institute of Technology
E-mail: hud@chemistry.gatech.edu
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812808
Angewandte Chemie International Edition
COMMUNICATION
2b,c). Clearly, although achiral, TAP/CyCo6 rosettes
spectroscopic features similar to those of the TAP/CyCo6
assemblies. As shown in Figure 3b, the CD spectra of thin film
gels formed from S(-) or R(+)-4-Me-CyCo6 and TAP are of
identical shape and magnitude, but of opposite sign. Unlike the
gels formed from TAP/CyCo6, 2D CD images of the gels
prepared from the chiral derivatives show no evidence of domains
and exhibit essentially the same CD signal across the sample
(Figure S10 and S11, see the Supporting Information).
spontaneously assemble into homochiral structures.
O
O
a)
H
N
H
N
H
H
N
H
N
N
H
H
H
O
O
N
H
N
H
N
H
H
N
H
O
N
N
N
N
N
O
H
O
H
N
N
H
O
O
N
H
O
H
N
H
N
H
N
+
O
or
N
N
H
H
H
H
O
O
N
N
H
N
H
H
H
O
N
N
N
N
H
H
O
O
N
O
N
N
H
H
O
O
O
b)140
120
Temperature (°C)
5
100
80
60
40
20
0
10
15
20
25
30
35
40
c)
200
225
250
275
300
325
Sample #
80
c)
1
5
9
60
40
11
17
20
30
33
39
20
0
-20
-40
-60
-80
500 nm
Figure 2 a) 2D circular dichroism image of a TAP-CyCo6 gel confined between
two quartz plates separated by 0.01 mm. Image was obtained by raster
scanning the sample cuvette in the path of the spectropolarimeter beam that
had been restricted to a cross-sectional diameter of 0.8 mm by an iris in the
beam path. b, c) SEM images showing helical bundles of stacked hexads within
a single sample of TAP-CyCo6 assemblies at two different imaging locations.
All samples contained 30 mM TAP and CyCo6, in 200 mM sodium phosphate
buffer (pH 7). Orange helical structures are idealized interpretations of the
structures boxed in panels (b) and (c).
200
225
250
275
300
325
Figure 1. a) Chemical structures of TAP and CyCo6, the hexad structure
formed by H-bonding of three monomers of each, and an illustration of helically
twisted stacked hexads. b) Circular dichroism spectra of a TAP-CyCo6 sample
(30 mM in each monomer) acquired at temperatures ranging from 5 to 40 °C.
c) Circular dichroism spectra of 40 independently made samples containing
TAP and CyCo6 (30 mM in each monomer) acquired at 20 °C.
We examined the effect of S(-) or R(+)-4-Me-CyCo6
“sergeants” on TAP/CyCo6 “soldiers”. Addition of small amounts
of these enantiomerically pure chiral analogs to a 1:1 mixture of
TAP and CyCo6 gave gels with the same CD intensity as gels
formed from the pure enantiomers (Figure 3b). Moreover, 2D CD
images of these samples confirm the formation of supramolecular
assemblies with one handedness across the entire sample
(Figures S12 and S13, see the Supporting Information). The
Sergeants and Soldiers effect has been widely examined in
various helical systems;[14] the maximum chiral amplification
previously reported is approximately 500 (i.e., one sergeant
commands 500 soldiers) [5a, 15] for both dynamic helical polymers
To assess the impact of a chiral center on the propensity of
these assemblies to produce helical stacks and twisted bundles,
we prepared both enantiomers of (4-methyl-6-(2,4,6-trioxo-1,3,5-
triazinan-1yl)hexanoic acid (R(+)-4-Me-CyCo6 and S(-)-4-Me-
CyCo6) (Figure 3a, Figures S4-S7, see the Supporting
Information). Hydrogels were formed upon combining TAP and
S(-) or R(+)-4-Me-CyCo6. Atomic force microscopy (AFM)
analysis of these gels revealed that they are also comprised of
linear, micron-length fibers (Figure S8 and S9, see the Supporting
Information). These supramolecular polymers form gels that have
This article is protected by copyright. All rights reserved.

10.1002/anie.201812808
Angewandte Chemie International Edition
COMMUNICATION
and supramolecular helical systems. We added various amounts
of either S(-) or R(+)-4-Me-CyCo6 to an assembled mixture of
TAP/CyCo6 in 200 mM phosphate buffer (the sum of CyCo6 and
4-Me-CyCo6 concentration was kept constant) and measured the
CD signal at 20 °C (Figure 3c). These experiments reveal that
replacement of only one CyCo6 of 1000 with an S(-) or R(+)-4-
Me-CyCo6 results in total alignment of the helical polymer. This
is the highest degree of chiral amplification ever reported for a
covalent or supramolecular polymer system.[16] Samples with
robust, unique single handedness are observed with as little as
0.1 mol% of added S(-) or R(+)-4-Me-CyCo6 . In multiple heating-
cooling cycles where the samples were cycled between 40 °C (a
temperature that causes complete disassembly of the fibers) and
20 °C (a temperature that supports formation of the fibers), these
assemblies were spontaneously reformed at 20 °C with the same
handedness (Figure S14, see the Supporting Information).
approach, an assembly is formed from a mixture of monomers
containing unequal amounts of the two enantiomers (Figure 3d).
The smaller the enantiomeric excess (ee) required to induce
homochirality in the assembly, the more powerfully the majority
rules. We prepared nearly racemic mixtures of S(-) and R(+)-4-
Me-CyCo6 and examined the gels they formed with TAP. The CD
spectra of these gels show that assemblies comprised of S(-) and
R(+)-4-Me-CyCo6 in a ratio of 53:47 (6% ee) have negative CD
signals with intensities essentially identical to those formed from
the pure enantiomer and with one handedness across the entire
sample (Figure S16-S18, see Supporting Information). The
single-handed helicity of these gels is maintained through multiple
heating and cooling cycles. Correspondingly, a similarly stable gel
formed with a 6% ee of R(+)-4-Me-CyCo6 exhibits the opposite
CD sign with equal intensity. Thus, these assemblies provide a
means for converting a small ee into a macroscopic homochiral
domain of stacked nucleic acid base-like heterocycles.
O
60
a)
b)
H
O
O
Our laboratory recently reported the spontaneous formation
of nucleoside and nucleotide analogs from the reaction of several
R(+)-4-Me-CyCo6
N
N
N
N
N
N
40
20
with TAP
O
N
H
O
CyCo6
plausibly prebiotic sugars and sugar phosphates with various N-
O
18]
heterocycles.[9,
enantiomers
For the current study, we prepared both
the nucleotide 5-β-ribofuranosyl-2,4,6-
H
O
O
0
O
N
H
O
of
-20
-40
-60
R(+)-4-Me-CyCo6
triaminopyrimidine, termed L-pTARC and D-pTARC (Figure 4a),
by the reaction of L- or D-ribose-5-phosphate with TAP.
Purification of these nucleotides gave a mixture of anomers
containing at least 95% of the b isomer. The structure of the
isolated pTARC nucleotides were confirmed to be b-furanosides
by NMR spectroscopy, as described previously,[18] (details of the
syntheses and purification are provided in the Supporting
Information, see Figures S19-S25).
O
S(-)-4-Me-CyCo6
with TAP
H
O
O
O
N
H
O
250 260 270 280 290 300
S(-)-4-Me-CyCo6
l / nm
75
50
25
0
100
c)
d)
75
50
R(+)-4-Me-CyCo6
25
0
-25
-50
-75
100
We examined the ability of added pTARC to affect the
chirality of TAP/CyCo6 assemblies. A CD signal appears in the
sample when pTARC is added (the sum of TAP and pTARC
concentration was kept constant) to mixtures of the achiral TAP-
CyCo6 monomers (Figures S26, see the Supporting Information).
Quantitative analysis revealed that replacement of one of 25 TAP
molecules with L-pTARC or D-pTARC results in the complete
alignment of the helical polymers. pTARC is a less powerful
sergeant than 4-Me-CyCo6; nevertheless, this is the first example
of chiral amplification of a supramolecular polymer by a
spontaneously formed plausibly prebiotic nucleotide.
Solutions that contain at least 60 mM L- or D-pTARC and
cyanuric acid (Cy) form hydrogels in phosphate buffer at pH 7 that
are analogous to those of TAP/CyCo6. AFM imaging confirms
that these hydrogels are comprised of micron-long pTARC-Cy
fibers (Figures S27-S28, see the Supporting Information). 2D CD
images of thin films of the gel formed from a racemic mixture of L-
and D-pTARC and Cy do not reveal the formation of homochiral
domains. However, gels formed from the pure enantiomers do
show bisignate CD signals with oppositely signed Cotton effects
(Figure 4b) with one handedness across the entire sample
(Figures S29 and 30, see the Supporting Information). AFM
images of these samples reveal left (M) and right (P) helices
(Figures 4d, 4e), respectively, for the L- and D-pTARC/Cy
assemblies. We prepared mixtures of L- and D- pTARC of various
ee and examined the gels they formed with Cy by CD
spectroscopy. The results of these experiments (Figure 4c) show
that a 30% majority of one enantiomer is sufficient to cause the
entire gel to adopt a single helical handedness (Figure S31, see
the Supporting Information). The homochirality of these gels is
robust; it is retained in assemblies even after multiple heating and
-25
-50
-75
S(-)-4-Me-CyCo6
0.0
0.5
1.0
1.5
2.0
-6
-4
-2
0
2
4
6
% chiral Me-CyCo6 monomer
Enantiomeric excess (%)
Figure 3. a) Structures of the chiral compounds R(+)-4-Me-CyCo6 and S(-)-4-
Me-CyCo6, with CyCo6 shown for comparison. b) CD spectra of assemblies
formed from 1:1 mixtures of 30 mM each of TAP and R(+)-4-Me-CyCo6 (black)
or S(-)-4-Me-CyCo6 (grey). c) The effect of S(-) or R(+)-4-Me-CyCo6
concentration on the CD signal intensity of (achiral) TAP-CyCo6 assemblies.
The sharp transition indicates that a 0.001 mole fraction of either chiral
compound is sufficient to drive the achiral CyCo6 (at a mole fraction of 0.999)
to form assemblies with a single handedness. d) The dependence of the CD
intensity on ee of assemblies composed of TAP and different ratios of S(-)-4-
Me-CyCo6 and R(+)-4-Me-CyCo6. Data were fit with an equation based on the
Ising model.[17] The best root-mean-square deviation (RMSD) fit (shown)
supports complete adoption of a single handedness of the assemblies for ee of
6%, and a domain size of ca. 720 CyCo6 monomers. Note that the midpoint of
this fit is offset approximately -0.5%, which is likely due to experimental errors
in monomer stock concentrations. The assemblies were prepared by mixing
individual components in a buffered solution, heating to 40 °C for complete
disassembly, and then cooling to 20 °C. All measurements were carried out on
samples that had been equilibrated for at least 8 hours after preparation.
Other chiral compounds are able to function as sergeants in
this system, but exhibit a less powerful influence. For example,
the addition of D- or L-arginine to TAP/CyCo6 assemblies induces
the formation of homochiral structures (Figure S15, see the
Supporting Information), but the addition of 2.5 equiv. of arginine
to these assemblies is required to achieve exclusively one
macroscopic homochiral domain.
The “Majority Rules” paradigm can also be applied to control
the handedness of TAP/4Me-CyCo6 assemblies. In this
This article is protected by copyright. All rights reserved.

10.1002/anie.201812808
Angewandte Chemie International Edition
COMMUNICATION
cooling cycles. This is the first report of a spontaneously formed
ribose phosphate substituted N-heterocycle that self-assembles
with an achiral partner in aqueous solution where a majority
enantiomer enforces formation of macroscopic domains of
homochiral polymers.
Acknowledgements
This work was supported by the NSF and the NASA Astrobiology
Program under the NASA/NSF Center for Chemical Evolution
[CHE-1504217]. We thank M. Srinivasarao for discussions and G.
Newnam and R. Bedell for technical assistance.
a)
D-pTARC
L-pTARC
Keywords: Symmetry breaking • homochirality • prebiotic •
chiral domains • chiral amplification
[1]
[2]
[a] M. Klussmann, D. G. Blackmond, in ACS Sym. Ser., Vol. 1025 (Eds.:
L. Zaikowski, J. M. Friedrich, S. R. Seidel), Washington, DC, 2009, pp.
133-145; [b] J. Buchs, L. Vogel, D. Janietz, M. Prehm, C. Tschierske,
Angew. Chem. Int. Ed. 2017, 56, 280-284.
b)
c)
20
20
15
10
5
D-pTARC with Cy
15
10
5
[a] L. X. Zeng, Y. J. He, Z. F. Dai, J. Wang, C. Q. Wang, Y. G. Yang, Sci
China Ser B 2009, 52, 1227-1234; [b] M. R. Molla, A. Das, S. Ghosh,
Chem. Comm. 2011, 47, 8934-8936; [c] A. Rananaware, D. D. La, M. Al
Kobaisi, R. S. Bhosale, S. V. Bhosale, S. V. Bhosale, Chem. Comm.
2016, 52, 10253-1.0256; [d] M. Alaasar, S. Poppe, Q. S. Dong, F. Liu, C.
Tschierske, Chem. Comm. 2016, 52, 13869-13872.
0
0
-5
-5
-10
-15
-20
-10
-15
-20
L-pTARC with Cy
225
250
275
300
325
-100-75 -50 -25
0
25 50 75 100
Enantiomeric excess (%)
l
/ nm
[3]
[a] M. M. Green, N. C. Peterson, T. Sato, A. Teramoto, R. Cook, S. Lifson,
Science 1995, 268, 1860-1866; [b] W. H. Braunlin, in Adv. Biophys.
Chem., Vol. 5 (Ed.: C. A. Bush), JAI Press Inc., Greenwich, 1995, pp. 89-
139; [c] S. R. Nam, H. Y. Lee, J.-I. Hong, Chem. Eur. J. 2008, 14, 6040-
6043; [d] M. M. Brister, M. Pollum, C. E. Crespo-Hernandez, Phys. Chem.
Chem. Phys. 2016, 18, 20097-20103.
d)
e)
[4]
[5]
[a] M. M. Green, B. A. Garetz, B. Munoz, H. Chang, S. Hoke, R. G. Cooks,
J. Am. Chem. Soc. 1995, 117, 4181-4182; [b] J. van Gestel, A. R. A.
Palmans, B. Titulaer, J. A. J. M. Vekemans, E. W. Meijer, J. Am. Chem.
Soc. 2005, 127, 5490-5494.
[a] M. A. Mateos-Timoneda, M. Crego-Calama, D. N. Reinhoudt, Chem.
Soc. Rev. 2004, 33, 363-372; [b] R. P. Lemieux, Chem. Soc. Rev. 2007,
36, 2033-2045; [c] M. Liu, L. Zhang, T. Wang, Chem. Rev. 2015, 115,
7304-7397; [d] C. Tschierske, G. Ungar, ChemPhysChem 2016, 17, 9-
26; [e] S. Diaz-Cabrera, Y. Dorca, J. Calbo, J. Arago, R. Gomez, E. Orti,
L. Sanchez, Chem. Eur. J. 2018, 24, 2826-2831.
200 nm
Figure 4. a) Structures of the enantiomeric nucleotides D-pTARC and L-pTARC.
b) Circular dichroism spectra of a 1:1 mixture of D-pTARC (black) or L-pTARC.
(grey) and cyanuric acid (Cy) in phosphate buffer at pH 7. c) The dependence
of CD intensity on the ee of assemblies of Cy with pTARC. d, e) Atomic force
microscopic images showing the right (P) and left (M) handed helices of the D-
pTARC-Cy and L-pTARC-Cy assemblies, respectively. Samples prepared as
described in the caption to Figure 3.
[6]
[7]
[a] L. Perez-Garcia, D. B. Amabilino, Chem. Soc. Rev. 2002, 31, 342-
356; [b] J. A. Raskatov, Chem. Euro. J. 2017, 23, 16920-16923.
P. J. M. Stals, P. A. Korevaar, M. A. J. Gillissen, T. F. A. de Greef, C. F.
C. Fitie, R. P. Sijbesma, A. R. A. Palmans, E. W. Meijer, Angew. Chem.
Int. Ed. 2012, 51, 11297-11301.
[8]
[9]
M. Kimura, T. Hatanaka, H. Nomoto, J. Takizawa, T. Fukawa, Y.
Tatewaki, H. Shirai, Chem. Mater. 2010, 22, 5732-5738.
[a] B. J. Cafferty, D. M. Fialho, J. Khanam, R. Krishnamurthy, N. V. Hud,
Nat. Commun. 2016, 7, 11328; [b] D. M. Fialho, K. C. Clarke, M. K. Moore,
G. B. Schuster, R. Krishnamurthy, N. V. Hud, Org. Biomol. Chem. 2018,
16, 1263-1271.
In conclusion, we have demonstrated the spontaneous
emergence of macroscopic homochiral domains of assemblies in
water at pH 7 from achiral heterocycles that have been proposed
to be precursors of the nucleobases.[9b, 18-19] These assemblies
are very sensitive to chiral amplification by compounds that may
plausibly have been present in low ee on the prebiotic Earth.[20]
Moreover, mixtures of spontaneously formed ribonucleotide
enantiomers having modest ee form homochiral, supramolecular
polymeric assemblies. These findings may help to resolve the
conundrum revealed by Orgel’s report that incorporation of the
“wrong” (i.e., opposite) enantiomer in a growing nucleic acid
polymer inhibits elongation.[21] That is, homochirality may have
evolved from domains of supramolecular polymers where facile
exchange of the wrong enantiomer was followed by covalent bond
formation. We are exploring this possibility.
[10] [a] B. J. Cafferty, R. R. Avirah, G. B. Schuster, N. V. Hud, Chem. Sci.
2014, 5, 4681-4686; [b] S. C. Karunakaran, B. J. Cafferty, M. Pelaez-
Fernandez, K. Neselu, I. Schmidt-Krey, A. Fernandez-Nieves, G. B.
Schuster, N. V. Hud, Polym. Chem. 2018, 9, 5268-5277.
[11] B. J. Cafferty, I. Gallego, M. C. Chen, K. I. Farley, R. Eritja, N. V. Hud, J.
Am. Chem. Soc. 2013, 135, 2447-2450.
[12] P. Mineo, V. Villari, E. Scamporrino, N. Micali, Soft Matter 2014, 10, 44-
47.
[13] [a] V. K. Praveen, S. S. Babu, C. Vijayakumar, R. Varghese, A.
Ajayaghosh, Bull. Chem. Soc. Jpn. 2008, 81, 1196-1211; [b] M.
Hifsudheen, R. K. Mishra, B. Vedhanarayanan, V. K. Praveen, A.
Ajayaghosh, Angew. Chem. Int. Ed. 2017, 56, 12634-12638.
[14] [a] A. R. A. Palmans, E. W. Meijer, Angew. Chem. Int. Ed. 2007, 46,
8948-8968; [b] A. J. Markvoort, H. M. M. ten Eikelder, P. A. J. Hilbers, T.
F. A. de Greef, E. W. Meijer, Nat. Commun. 2011, 2, 509; [c] E. Yashima,
N. Ousaka, D. Taura, K. Shimomura, T. Ikai, K. Maeda, Chem. Rev. 2016,
116, 13752-13990.
[15] [a] M. A. Mateos-Timoneda, M. Crego-Calama, D. N. Reinhoudt,
Supramol. Chem. 2005, 17, 67-79; [b] M. A. Mateos-Timoneda, M.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812808
Angewandte Chemie International Edition
COMMUNICATION
Crego-Calama, D. N. Reinhoudt, Chem. Eur. J. 2006, 12, 2630-2638; [c]
T. Kim, T. Mori, T. Aida, D. Miyajima, Chem. Sci. 2016, 7, 6689-6694.
[16] Greater chiral amplification values can be observed in autocatalytic
systems, see K. Soai, T. Shibata, H. Morioka, K. Choji, Nature 1995, 378,
767-768.
[17] J. V. Selinger, R. L. B. Selinger, Phys. Rev. Lett. 1996, 76, 58-61.
[18] M. C. Chen, B. J. Cafferty, I. Mamajanov, I. Gállego, J. Khanam, R.
Krishnamurthy, N. V. Hud, J. Am. Chem. Soc. 2014, 136, 5640-5646.
[19] B. J. Cafferty, N. V. Hud, Isr. J. Chem. 2015, 55, 891-905.
[20] J. R. Cronin, S. Pizzarello, Science 1997, 275, 951-955.
[21] G. F. Joyce, A. W. Schwartz, S. L. Miller, L. E. Orgel, Proc. Natl. Acad.
Sci. USA 1987, 84, 4398-4402.
This article is protected by copyright. All rights reserved.

10.1002/anie.201812808
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
COMMUNICATION
Homochiral domains appear in
supramolecular assemblies formed
by the achiral monomers 2,4,6-
triaminopyrimimidine and a
modified cyanuric acid; these
samples become uniformly
homochiral when as little as 0.1%
of a chiral cyanuric acid monomer
is added, or when there is at least
a 6% ee in samples containing
both enantiomers of the chiral
monomer.
Suneesh C. Karunakaran,
Brian J. Cafferty, Angela Weigert-
Muñoz, Gary B. Schuster and
Nicholas V. Hud*
Page No. – Page No.
Spontaneous Symmetry Breaking
in the Formation of
Supramolecular Polymers:
Implications for the Origin of
Biological Homochirality
This article is protected by copyright. All rights reserved.