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Possible chemical and physical scenarios towards

biological homochirality†
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51, 3436
Quentin Sallembien, *a Laurent Bouteiller, a
Jeanne Crassous *b and
Matthieu Raynal *a

The single chirality of biological molecules in terrestrial biology raises more questions than certitudes
about its origin. The emergence of biological homochirality (BH) and its connection with the appearance
of life have elicited a large number of theories related to the generation, amplification and preservation
of a chiral bias in molecules of life under prebiotically relevant conditions. However, a global scenario is
still lacking. Here, the possibility of inducing a significant chiral bias ‘‘from scratch’’, i.e. in the absence of
pre-existing enantiomerically-enriched chemical species, will be considered first. It includes phenomena
that are inherent to the nature of matter itself, such as the infinitesimal energy difference between
enantiomers as a result of violation of parity in certain fundamental interactions, and physicochemical
processes related to interactions between chiral organic molecules and physical fields, polarized
particles, polarized spins and chiral surfaces. The spontaneous emergence of chirality in the absence of
detectable chiral physical and chemical sources has recently undergone significant advances thanks to
the deracemization of conglomerates through Viedma ripening and asymmetric auto-catalysis with the
Soai reaction. All these phenomena are commonly discussed as plausible sources of asymmetry under
prebiotic conditions and are potentially accountable for the primeval chiral bias in molecules of life.
Then, several scenarios will be discussed that are aimed to reflect the different debates about the
emergence of BH: extra-terrestrial or terrestrial origin (where?), nature of the mechanisms leading to the
propagation and enhancement of the primeval chiral bias (how?) and temporal sequence between
chemical homochirality, BH and life emergence (when?). Intense and ongoing theories regarding the
emergence of optically pure molecules at different moments of the evolution process towards life, i.e. at
the levels of building blocks of Life, of the instructed or functional polymers, or even later at the stage of
more elaborated chemical systems, will be critically discussed. The underlying principles and the
Received 24th December 2021 experimental evidence will be commented for each scenario with particular attention on those leading
DOI: 10.1039/d1cs01179k to the induction and enhancement of enantiomeric excesses in proteinogenic amino acids, natural
sugars, and their intermediates or derivatives. The aim of this review is to propose an updated and timely
rsc.li/chem-soc-rev synopsis in order to stimulate new efforts in this interdisciplinary field.

1. Introduction possesses no symmetry elements of the second kind (i.e. if it is

devoid of any improper axis of rotation).2 Whilst the manifesta-
In 1884, Lord Kelvin used the word chirality—derived from the tion of chirality at the macroscopic scale sparked human’s
Proto-Indo-European *ǵhesr through the Ancient Greek weir curiosity from antiquity, its observation at the molecular and
(kheı́r), which both mean ‘hand’—and gave the following sub-atomic levels is relatively recent. In the 19th-century,
definition: ‘‘an object is chiral if and only if it is not super- advances made in optics,3 crystallography4 and chemistry5
imposable on its mirror image’’.1 Additionally, chirality can be paved the way to the scientific study of molecular chirality
described based on symmetry aspects: an object is chiral if it (named ‘molecular dissymmetry’ by Louis Pasteur)6 which soon
after manifested itself in a variety of studied phenomena. The
a
Sorbonne Université, CNRS, Institut Parisien de Chimie Moléculaire, term ‘‘chirality’’ took additionally almost 80 years to be intro-
Equipe Chimie des Polymères, 4 Place Jussieu, 75005 Paris, France. duced in chemistry by Kurt Mislow (1962).7
E-mail: quentin.sallembien.2017@enscbp.fr,
Chirality is found at all scales in matter, from elementary
matthieu.raynal@sorbonne-universite.fr
b
Univ Rennes, CNRS, Institut des Sciences Chimiques de Rennes, ISCR-UMR 6226,
particles to cucumber tendrils,8 from screws to spiral galaxies,
F-35000 Rennes, France. E-mail: jeanne.crassous@univ-rennes1.fr in living and inert systems.9 It is also an everyday concern in
† Dedicated to the memory of Sandra Pizzarello (1933–2021). industry (e.g. pharma, agribusiness, and cosmetics)10–14 as well

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as in fundamental research (visible in countless conferences homochirality in Nature is considered as a stereochemical

encompassing not only chemistry, physics, and biology but also imperative.17 For example, D-sugars are building blocks of
economy and arts).15 helically shaped DNA and RNA macromolecules, which store
Homochirality of life refers to the fact that Nature has genetic information and encode the synthesis of proteins
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chosen a specific handedness. Homochirality is a fascinating through the ligation of their constituting amino acids. Glucose
aspect of terrestrial biology: all living systems are composed of
L-amino acids and D-sugars‡ to such an elevated extent that the ‡ Proteinogenic amino acids and natural sugars are usually mentioned as
occurrence of the molecules of life with different configurations L-amino acids and D-sugars according to the descriptors introduced by Emil

(e.g. D-amino acids) is seen as a curiosity.16 Clearly, the perfect Fischer. It is worth noting that natural L-cysteine (R) uses the Cahn–Ingold–Prelog
system, due to the sulfur atom in the side chain which changes the priority
level of selectivity reached by evolution and preserved along
sequence. In the present review, (R)/(S) and D/L descriptors will be used for amino
billion years, is out of reach for currently developed artificial
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acids and sugars, respectively, as commonly employed in the literature dealing

systems. Homochirality and life are so closely related that with BH.

Quentin Sallembien was born in Laurent Bouteiller is the CNRS

1993 in Strasbourg, France. He Research Director and head of
got an engineering diploma from the Polymer Chemistry lab at
ENSCBP – Bordeaux INP (2017) Sorbonne Université in Paris.
and obtained in 2021 a doctoral His main research interests are
degree under the supervision of focused on the interface between
Dr Matthieu Raynal (Sorbonne polymer science and supramole-
Université). His PhD research cular chemistry, which involves
focused on controlling the hand- using non-covalent interactions
edness of supramolecular helical to assemble molecules. The low
polymers by means of circularly energies involved make it possible
polarized light and chiral addi- to control the formation of
Quentin Sallembien tives. He is currently a postdoc- Laurent Bouteiller complex architectures and to
toral researcher in the group of obtain materials with reversible
Prof. Renaud Nicolaÿ at ESPCI properties of interest in various fields (e.g. rheology, catalysis,
Paris, dealing with polyolefin adhesion, and coatings).
vitrimers.

Dr Jeanne Crassous (born Costante) Matthieu Raynal got his PhD

received her PhD in 1996 under the degree under the supervision
supervision of Prof. André collet of Dr P. Braunstein in 2009
(ENS, Lyon, France), working on (Strasbourg). He conducted post-
the absolute configuration of doctoral studies at UPMC with
bromochlorofluoromethane. After a L. Bouteiller (Paris) and in the
one-year postdoctoral period group of Prof. P. W. N. M. van
studying the chirality of fullerenes Leeuwen at ICIQ (Tarragona,
in Prof. François Diederich’s group Spain). In 2012, he was appoin-
(ETH Zurich, Switzerland), she was ted as a CNRS researcher at
appointed a CNRS researcher at the Sorbonne Université, Paris. He is
ENS Lyon in 1998. In 2005, she fascinated by how non-covalent
Jeanne Crassous joined the ‘‘Institut des Sciences Matthieu Raynal interactions can be designed to
Chimiques de Rennes’’ (University control the outcome of a cata-
of Rennes, France) and was appointed a CNRS Director of Research in lytic reaction, i.e. supramolecular catalysis. His group is curr-
2010. Her group works on many fields related to chirality ently developing supramolecular helical catalysts with particular
(organometallic and heteroatomic helicenes, fundamental aspects of efforts devoted to improving their chirality amplification and
chirality such as parity violation effects, chiroptical activity such as switchable properties. His research activities also concern the
electronic and vibrational circular dichroism and circularly polarized design of functional chiral assemblies and the structure–property
luminescence). In 2020, she received the National Prize of the Organic relationship of supramolecular polymers. He recently co-edited
Chemistry Division of the French Chemical Society (DCO-SCF). with P. W. N. M. van Leeuwen the book ‘‘Supramolecular
Catalysis: New Directions and Developments’’ (2022 Wiley-VCH
GmbH).

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monomers in glycogen, starch and cellulose also have a direction of the same enantiomer for a given racemate,
D configuration. This suggests that the chirality, structure, and as a result of parity violation in certain interactions within
functions of these biomacromolecules are intimately related.18 nuclei.53,54 The second category (ii) refers to natural physical
In 1857, Louis Pasteur revealed the dramatic difference in fields (gravitational, magnetic, and electric), light and their
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the fermentation rate of two tartaric acid enantiomers with a combinations, which under certain conditions constitute truly
yeast microorganism, thus uncovering biological enantio- chiral fields,30 but also to a range of inherently chiral sources
selectivity.19–21 Pasteur was convinced that chirality was a such as chiral light and polarized particles (mostly electrons),
manifestation of life, and unsuccessfully looked for the link polarized electron spins, vortices, or surfaces.44 The third
between physical forces ruling out the Cosmos and the mole- category (iii) encompasses processes that lead to the sponta-
cular dissymmetry observed in natural products. In 1886, neous emergence of chirality in the absence of detectable chiral
an Italian chemist Arnaldo Piutti22 succeeded in isolating
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physical and chemical sources, upon destabilization of the

(R)-asparagine, mirror-image of the tasteless amino-acid racemic state and stabilization of a scalemic or homochiral
(S)-asparagine, and found that it was intensely sweet.23 These state. Such spontaneous mirror symmetry breaking (SMSB)
discoveries refer to the link between the handedness of chiral phenomena40 involve interactions between molecules through
substances and their biological properties but do not explain auto-catalytic processes which under far-from-equilibrium con-
the origin of biological homochirality (BH). ditions may lead to the emergence of enantiopure molecules.
Despite the extensive literature, the emergence of BH The topic has recently undergone significant progress thanks to
remains a conundrum.24–44 The key points of this intricate numerous theoretical models and experimental validations,
topic can be summarized as: how, when and where did single namely the deracemization of conglomerates through Viedma
chirality appear and eventually lead to the emergence of life ripening55 and the asymmetric auto-catalysis with the Soai
(Fig. 1).45–48 Along this line, the question of the creation of the reaction.56 Importantly, the plausibility of the aforementioned
original chiral bias appears critical (box ‘‘how?’’ in Fig. 1). Huge chirality induction processes in the context of BH will depend
efforts have been dedicated to decipher which processes on several parameters such as: the extent of asymmetric induc-
may lead to the generation of a chiral bias without the action tion they may provide, their mode of action, i.e. if they are
of pre-existing enantiomerically enriched chemical species, unidirectional (deterministic towards a single enantiomer) or
that is without using the commonly employed routes in stereo- bidirectional (leading to either type of enantiomers), their
selective synthesis. The creation of a chiral bias ‘‘from scratch’’, relevance according to prebiotic conditions present on earth 4
often referred to as absolute asymmetric synthesis30,31,49,50 and billion years ago, the scope of molecules it could be applied to,
spontaneous deracemization,41,51,52 actually encompasses a and their validation by experimental evidence. The first three
large variety of phenomena. Here, a distinction can be made parts of this review will provide an updated version of pheno-
between chiral biases that: (i) are inherent to the nature of matter mena i–iii that are commonly discussed as plausible sources
itself, (ii) originate from the interaction of molecules with physical of asymmetry under prebiotic conditions and can thus be
fields, particles, spins or surfaces, or (iii) emerge from the mutual potentially accountable for the primeval chiral bias in mole-
interaction between molecules (Fig. 1). The first category (i) corres- cules of life.
ponds to the fact that a racemate deviates infinitesimally However, uncovering plausible mechanisms towards the
from its ideal equimolar composition deterministically, i.e. in emergence of a chiral bias is not enough per se for elucidating

Fig. 1 Schematic representation of the questions and potential answers which are fundamentally related to the conundrum of the origin of the
homochirality of life. This review is divided into 4 parts as indicated in the scheme. PVED: parity-violating energy difference. SMSB: spontaneous mirror
symmetry breaking.

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the origin of BH. Additional fundamental challenges such as reflection is a distorted representation of the reality. The
the extra-terrestrial or terrestrial origin of molecule of life perception of a different nature of mirror-image objects is also
precursors (box ‘‘where?’’ in Fig. 1), the mechanism(s) for the found in the modern literature. In his famous novel ‘‘Through
propagation and enhancement of the original chiral bias (box the Looking-Glass’’ by Lewis Caroll Alice raises important
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‘‘how 2?’’ in Fig. 1) and the chemical/biological pathways questions: ‘How would you like to live in Looking-glass House,
leading to functional bio-relevant molecules are key aspects Kitty? I wonder if they’d give you milk in there? Perhaps
to propose a credible scenario. The detection of amino acids Looking-glass milk isn’t good to drink. . .’’
and sugars with preferred L and D configurations, respectively, The Universe is constituted of elementary particles which
on carbonaceous meteorites57 instigated further research for interact through fundamental forces, namely the electromag-
determining plausible mechanisms for the production of chiral netic, strong, weak, and gravitational forces. Until the mid-20th
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molecules in an interstellar environment and their subsequent century, fundamental interactions were thought to equally
enantiomeric enrichment.58,59 Alternatively, hydrothermal operate in a physical system and its image built through space
vents in primeval oceans constitute an example of reaction inversion. Indeed, these laws were assumed by physicists to be
domains often evoked for prebiotic chemistry which may also conserved under the parity operator P (which transforms the
include potential sources of asymmetry such as high-speed spatial coordinates x, y, z into x, y, z), i.e. parity-even.
microvortices.60 Some mechanisms are known for increasing However, in 1956, Lee and Yang highlighted that parity was
an existing e.e., such as the self-disproportionation of enantio- only conserved for strong and electromagnetic forces, and
mers (SDE),61 non-linear effects in asymmetric catalysis,62,63 proposed experiments to test it for weak interactions.66 A few
and stereoselective polymerization.64 Noteworthy in the present months later, Wu experimentally demonstrated that the parity
context, these processes may be applied to increase the optical symmetry is indeed broken in weak forces (which are hereby
purity of prebiotically relevant molecules. However, a general parity-odd),67 by showing that the transformation of unstable
amplification scheme which is valid for all molecules of life is 60
Co nuclei into 60Ni, through the b-decay of a neutron into a
lacking. proton, emits electrons of only left-handedness. In fact, solely
The temporal sequence between chemical homochirality, left-handed electrons were emitted since W+ and W bosons
BH and life emergence is another intricate point (box ‘‘when?’’ (abbreviated as W bosons), which mediate the weak charged-
in Fig. 1). Tentative explanations try to build-up either abiotic current interactions, only couple with left-handed particles.
theories considering that single chirality is created before the Right-handed particles are not affected by weak interactions
living systems or biotic theories suggesting that life preceded carried out by W bosons and consequently, neutrinos, that are
homochirality.44 Purely abiotic theories refer to reactions or only generated by processes mediated by W bosons, are all
physicochemical processes involving low-molecular weight left-handed in the universe.68
organic molecules presumably present in the prebiotic The weak neutral current interactions, mediated by the Z0
soup.38,65 From a different angle, polymerization of activated boson (sometimes called Z forces), are without charge exchange
building blocks is also discussed as a possible stage for the and, just like the charged ones, violate the parity symmetry.69–73
induction/enhancement of chirality,64 even though prebiotic Thus, all weak interactions, carried out by W or Z0 bosons,
mechanisms towards these essential-to-life macromolecules break the fundamental parity symmetry.
remain highly elusive.45–48 In the fifth part of this review, we Parity violation has been observed in nuclear67 and atomic
will propose an update of the most plausible chemical and Physics.74–77 In consequence, the contribution of the Z force
physical scenarios towards BH, with emphasis on the under- between the nuclei and electrons produces an energy shift
lying principles and the experimental evidence, showing merits between the two enantiomers of a chiral molecule. The lower-
and limitations of each mechanism. Notably, relevant experi- energy enantiomer would thus be present in slight excess in an
mental investigations conducted with building blocks of life: equilibrium mixture; this imbalance may provide a clue to the
proteinogenic amino acids, natural sugars, and their inter- origin of biomolecular homochirality, i.e. why chiral molecules
mediates or derivatives, will be commented in regards of the usually occur in a single enantiomeric form in nature. Such a
different scenarios. tiny parity violation energy difference (a PVED of about 1017
Ultimately, the aim of this literature review is to familiarize kT at 300 K) should be measurable by any absorption spectro-
the novice with research dealing with BH, and to propose scopy provided that ultra-high resolution can be reached.78–81
to the expert an updated and timely synopsis of this inter- Over the past decades, various experiments have been proposed
disciplinary field. to observe parity violation in chiral molecules, including mea-
surements of PV frequency shifts in NMR spectroscopy,82
measurements of time dependence of optical activity,83 and
2. Parity violation (PV) and parity- direct measurement of the absolute PV energy shift of the
violating energy difference (PVED) electronic ground state.79–81,84
However, it has never been unequivocally observed at the
‘‘Videmus nunc per speculum in aenigmate,’’ (Holy Bible, I Cor. molecular level to date. Note that symmetry violation of time
XIII, 12) which can be translated into ‘‘At present, we see reversal (T) and of charge parity (CP) is actually recovered in the
indistinctly, as in a mirror’’ refers to the intuition that a mirror CPT symmetry, i.e., in the ‘‘space-inverted anti-world made of

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antimatter’’.85 Quantitative calculations of this parity-violating

energy difference between enantiomers have been improved
during the last four decades,86–90 to give for example about
1012 J mol1 for CHFClBr.91,92 Although groups of Crassous/
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Darquié in France78,93–98 and Quack in Switzerland99–103 have

been pursuing an experimental effort to measure PVED, thanks
to approaches based on spectroscopic techniques and/or tun-
neling processes, no observation has unambiguously con-
firmed it yet. However, thanks to the combination of the
contribution from the weak interaction Hamiltonian (Z3) and
from the spin orbit coupling (Z2), the parity violating energy
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difference strongly increases with increasing nuclear charge

with a commonly accepted Z5 scaling law, thus chiral heavy
metal complexes might be favourable candidates for future
observation of PV effects in chiral molecules.94,96 Other types
of experiments have been proposed to measure PV effects, such
as nuclear magnetic resonance (NMR), electron paramagnetic
resonance (EPR), microwave (MW) or Mössbauer spectro-
scopy.79 Note that other phenomena have been taken into
consideration to measure PVED such as in Bose–Einstein
condensation, but those were not conclusive.104,105 Fig. 2 Distinction between ‘‘true’’ and ‘‘false’’ chirality30,130 by considering
The tempting idea that PVED could be the source of the tiny the effect of parity (P) and time (T) reversal on spinning cones (a) and
enantiomeric excess amplified to the asymmetry of life was put aligned magnetic and electric fields (b).

forward by Ulbricht in 1959106,107 and by Yamagata in 1966.108

With this in mind, Mason, Tranter and MacDermott109–122
defended in the eighties and early nineties that (S)-amino acids, true and false chirality as follows: the ‘‘true chirality is shown
D-sugars, a-helix or b-sheet secondary structures, and other by systems existing in two distinct enantiomeric states that are
natural products and secondary structures of biological impor- interconverted by space inversion (P), but not by time reversal (T)
tance are more stable than their enantiomorph due to PVED.54 combined with any proper spatial rotation (Rp)’’.130 Along this
However, Quack89,123 and Schwerdtfeger124,125 independently line, stationary and translating rotating cones are prototypical
refuted these results on the strength of finer calculations, and representations of false and true chirality, respectively (Fig. 2a).
Lente126,127 asserted that a PVED of around 1013 J mol1 Cones help to better visualize the true chiral nature of vortices, but
causes an excess of only 6  106 molecules in one mole (against the concept is actually valid for any translating spinning objects,
1.9  1011 for the standard deviation). In reply, MacDermott e.g. photons and electrons.85,131 All experimental attempts to
claimed, by means of a new generation of PVED computations, produce any chiral bias using a static uniform magnetic or electric
that the enantiomeric excess of four gaseous amino acids found field, or unpolarized light failed and this can be explained by the
in the Murchison meteorite (in the solid state) could originate non-chiral nature of these fields.30,31,49 In addition, the combination
from their PVED.128,129 Whether PVED could have provided a of static uniform magnetic and electric fields, whatever parallel
sufficient bias for the emergence of BH likely depends on the or antiparallel, constitutes another example of false chirality
related amplification mechanism, a point that will be discussed (Fig. 2b).30
in more detail in part 4. Importantly, only when interacting with a truly chiral system
the energy of enantiomeric probes can be different (corres-
ponding to diastereomeric situations), while no loss of degen-
3. Chiral fields eration in energy levels can happen in a falsely chiral system;
however, asymmetry could be obtained for processes out of
Physical fields, polarized particles, polarized spins and surfaces thermodynamic equilibrium.30,31 Based on these definitions,
are commonly discussed as potential chiral inducers of enan- truly chiral forces may lift the degeneracy of enantiomers and
tiomeric excesses in organic molecules. The aim of this part is induce enantioselection in a reaction system reaching its sta-
to present selected chiral fields along with experimental obser- tionary state, while an influence of false chirality is only
vations which are relevant in the context of elucidating BH. possible for kinetically controlled reaction outputs, since in
this case the enantiomers remain strictly degenerate and only
3.1 Physical fields the breakdown of the reaction path microreversibility occurs.41
(a) True and false chirality. Chirality’s definitions based on Furthermore, the extent of chiral induction that can be
symmetry arguments are adequate for stationary objects, but achieved by a chiral physical field is intimately related to the
not when motion comes into play. To address the potential nature of its interaction with matter, i.e. with prebiotically
chiral discriminating nature of physical fields, Barron defined relevant organic molecules in the context of BH. A few examples

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of physical fields for absolute asymmetric synthesis are men-

tioned in the next paragraphs.
(b) Magnetochiral effects. A light beam of arbitrary polar-
ization (with k as the wavevector) propagating parallel to a
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static magnetic field (B) also possesses true chirality (kB),

exploited by the magneto-chiral dichroism (MChD, Fig. 3a).132
MChD was first observed by Rikken and Raupach in 1997 for
a chiral europium(III) complex, and was further extended to
other metal compounds and a few aggregates of organic
molecules.132–136 Photoresolution of D- and L-chromium(III)
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tris(oxalato) complexes thanks to magnetochiral anisotropy

was accomplished in 2000 by the same authors,137 with an
enantioenrichment proportional to the magnetic field, e.e./B
being equal to 1  105 T1 (Fig. 4b).
(c) Mechanical chiral interactions. Whilst mechanical
interactions of chiral objects with their environment is well
established at the macroscale, the ability of these interactions
to mediate the separation of molecular enantiomers remains
largely under-explored.139 A few experimental reports indicate
that fluid flows can discriminate not only large chiral
objects,140–142 but also helical bacteria,143 colloidal particles,144
and supramolecular aggregates.145,146 It has been indeed found
that vortices, being induced by stirring, microfluidics or tem-
perature gradients, are capable of controlling the handedness of
supramolecular helical assemblies.60,145–159 Laminar vortices
Fig. 4 (a) Schematic representation of the experimental set-up for
the separation of chiral molecules placed in a microfluidic capillary
surrounded by rotating electric fields (A–D electrodes). (b) Expected
directions of motion of the enantiomers of 1,1 0 -bi-2-naphthol
bis(trifluoromethanesulfonate) for the indicated direction of rotation of
REF (curved black arrow). a is the relative angle between the electric dipole
moment and electric field. The grey arrows show the opposite directions
of motion of the enantiomers. (c) Absorbance chromatogram from the
in-line detector of a slug of (rac)-1,1 0 -bi-2-naphthol bis(trifluoromethane-
sulfonate) after exposure to clockwise REF for 45 h. The sample collected
from the shaded left side of the chromatogram had an e.e. of 26% in favour
of the (S) enantiomer, while the right shaded section of the chromatogram
had an e.e. of 61% for the (R) enantiomer. Reprinted ref. 138. Copyright
2015. Springer Nature under Creative Commons Attribution 4.0 Inter-
national License https://creativecommons.org/licenses/by/4.0/.

have been recently employed as the single chiral discriminating

source for the emergence of homochiral supramolecular gels
in milliseconds.60 High speed vortices have been evoked as
potential sources of asymmetry present in hydrothermal vents,
presumed key reaction sites for the generation of prebiotic
molecules. However, the propensity of shear flow to prevent
the Brownian motion and allow for the discrimination of small
molecules remains to be demonstrated. Grzybowski and
co-workers showed that s-shaped mm-sized particles located at
the oil/air interface parallel to the shear plane migrate to
different positions in a Couette cell.160 The proposed chiral drift
Fig. 3 (a) Schematic representation of MChD for a racemate of a metal mechanism may in principle allow the separation of smaller
complex: the unpolarised light is preferentially absorbed by L versus D chiral objects, with size in the order of tens of nanometres.
enantiomers. Reprinted from ref. 136 with permission from Wiley-VCH,
In 2015, a new molecular parameter called hydrodynamic
copyright 2020. (b) Photoresolution of the chromium(III) tris(oxalato)
complex. Plot of the e.e. after irradiation with unpolarised light for 25 min
chirality was introduced to characterize the coupling of rota-
at l = 695.5 nm, as a function of the magnetic field, with an irradiation tional motion of a chiral molecule to its translational motion
direction k, either parallel or perpendicular to the magnetic field.137 and quantify the direction and velocity of such motion.138

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The concept concerns the possibility to control the motion of (e) Through plasma-triggered chemical reactions. Plasma,
chiral molecules by orienting and aligning their dipole moment produced by the impact of extra-terrestrial objects on earth, has
with the electric field position leading to their rotation. The been investigated as a potential source of asymmetry. Price and
so-called molecular propeller effect allows enantiomers of two Furukawa teams reported, in 2013 and 2015, respectively, that
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binaphthyl derivatives, upon exposition to rotating electric fields nucleobases and/or proteinogenic amino acids were formed
(REF), to propel in opposite directions, leading to a local under conditions which presumably reproduced the conditions
enrichment of up to 60% e.e. (Fig. 4). It would be essential to of impact of celestial bodies on primitive earth.162,163 When
probe the interactions of vortices, shear flows and rotating shocked with a steel projectile fired at high velocities in a light
physical fields with biologically relevant molecules in order to gas gun, ice mixtures made of NH4OH, CO2 and CH3OH, were
uncover whether they could have played a role in the emergence found to produce equal amounts of (R)- and (S)-alanine,
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of a chiral bias on early earth. a-aminoisobutyric acid and isovaline as well as their pre-
(d) Combined action of gravity, magnetic field and rota- cursors.162 Importantly, only the impact shock is responsible for
tion. Micali et al. demonstrated in 2012 that the combination of the formation of amino-acids because post-shot heating is not
gravity, magnetic field and rotation can be used to direct the sufficient. A richer variety of organic molecules, including
handedness of supramolecular helices generated upon assem- nucleobases, were obtained by shocking ammonium bicarbo-
bly of an achiral porphyrin monomer (TPPS3, Fig. 5).161 It was nate solution under nitrogen (representative of the Hadean
presumed that the enantiomeric excess generated at the onset ocean and its atmosphere) with various metallic projectiles
of aggregation was amplified by the autocatalytic growth of the (as simplified meteorite materials).163 The production of
particles during the elongation step. The observed chirality is amino-acids is correlated with the concentration of ammonium
correlated to the relative orientation of the angular momentum bicarbonate, acting as the C1-source. The attained pressure and
and the effective gravity, the direction of the former being set by temperature (up to 60 GPa and thousands Kelvin) allowed
clockwise or anticlockwise rotation. The role of the magnetic chemical reactions to proceed, as well as racemization as
field is fundamentally different than that in the MChD effect evidenced later,164 but were not enough to trigger plasma
(Part 3.1(a)) since its direction does not influence the sign of processes. A meteorite impact was reproduced in the laboratory
the chiral bias. Its role is to provide tunable magnetic levitation by Wurz and co-workers in 2016,165 by firing projectiles of pure
13
force and alignment of the supramolecular assemblies. These C synthetic diamond to a multilayer target consisting of
results therefore seem to validate experimentally the prediction ammonium nitrate, graphite and steel. The impact generated
by Barron that false chiral influence may lead to absolute a pressure of 170 GPa and a temperature of 3 to 4  104 K,
asymmetric synthesis after enhancement of an initial chiral enough to form a plasma torch, through the interaction
bias created under far-from-equilibrium conditions.130 Accord- between the projectile and target materials and their subse-
ing to the authors, control experiments performed in the quent atomization and ionization. The most striking result is
absence of magnetic field discard the macroscopic hydro- certainly the formation of 13C-enriched alanine which is
dynamic chiral flow, i.e. a true chiral force (see Part 3.1(c)), as claimed to be obtained with e.e. values ranging from 7 to
the driving force for chirality induction; a point that has been 25%. The exact source of asymmetry is uncertain: the far-
recently disputed by other authors.41 Regardless of the true of from-equilibrium nature of the plasma-triggered reactions
false nature of the combined action of gravity, magnetic field and the presence of spontaneously generated electromagnetic
and rotation, its potential connection to BH is hard to conceive fields in the reactive plasma torch may have led to the observed
at this stage. chiral biases.166 This first report of an impact-produced enantio-
enrichment needs to be confirmed experimentally and supported
theoretically.

3.2 Polarized radiations and spins

(a) Circularly polarized light (CPL). A long time before the
discussions on the true or false chiral nature of physical fields,
Le Bel and van’t Hoff already proposed, at the end of the
nineteenth century, to use circularly polarized light, a truly
chiral electromagnetic wave existing in two enantiomorphic
forms (i.e. the left- and right-handed CPL), as chiral bias to
induce enantiomeric excess.31,167–169 Cotton strengthened this
idea in 1895,170–172 when he reported the circular dichroism (CD)
of an aqueous solution of potassium chromium(III) tartrate.
Circular dichroism is a phenomenon, corresponding to the
Fig. 5 Control of the handedness of TPPS3 helical assemblies by the
differential absorption of l-CPL and r-CPL at a given wavelength
relative orientation of the angular momentum of rotation (L) and the
effective gravity (Geff). TPPS3: tris-(4-sulfonatophenyl)phenyl porphyrin.
in the absorption region of an optically active material, as well
Reprinted from ref. 161 with permission from Nature publishing group, the spectroscopic method that measures it.173,174 Enantiomers
copyright 2012. absorbing CPL of one handedness constitute non-degenerated

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diastereoisomeric systems, based on the interaction between concentration in enantiomers (CR + CS) is constant during photo-
two distinct chiral influences, one chemical and the other resolution, the photostationary state (pss) is reached after pro-
physical. Thus, one state of this system is energetically longed irradiation irrespective of the initial enantiomeric
favoured, and one enantiomer preferentially absorbs CPL of composition.177 In the absence of side reactions, the pss is reached
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

one polarization state (l- or r-CPL). for eRCR = eSCS, which allows e.e. pss to be determined, e.e. at the
The dimensionless Kuhn anisotropy (or dissymmetry) photostationary state, as being equal to (CR  CS)/(CR + CS)= g/2.
factor g allows the quantitative description of the chiroptical Asymmetric photosynthesis (also called asymmetric fixation) pro-
response of enantiomers (eqn (1)). The Kuhn anisotropy duces an enantio-enriched product by preferentially reacting one
factor is expressed by the ratio between the difference in enantiomer of a substrate undergoing fast racemization (Fig. 6c).
molar extinction coefficients of l-CPL and r-CPL (De), and the Under these conditions, the (R)/(S) ratio of the product is equal to
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global molar extinction coefficient (e), where eL and eR are the the excitation ratio eR/eS, and the e.e. of the photoproduct is thus
molar extinction coefficients for left- and right-handed CPL, equal to g/2. The chiral bias which can be reached in asymmetric
respectively.175 It ranges from 2 to +2, for a total absorption photosynthesis and photoresolution processes is thus related to
of right- and left-handed CPL, respectively, and is wavelength the g value of enantiomers, whereas the e.e. in asymmetric
dependent. Enantiomers have equal but opposite g values, photolysis is influenced by both g and x values.
corresponding to their preferential absorption of one CPL The first CPL-induced asymmetric partial resolution dates
handedness. back to 1968 thanks to Stevenson and Verdieck, who worked
with octahedral oxalato complexes of chromium(III).179 Asym-
De eL  eR
g¼ ¼ e þ e  (1) metric photoresolution was further investigated for small
e L R
organic molecules,180,181 macromolecules182 and supramolecular
2
assemblies.183 A number of functional groups such as over-
The preferential excitation of one over the other enantiomer in crowded alkene, azobenzene, diarylethene, a,b-unsaturated
the presence of CPL allows the emergence of a chiral imbalance ketone or fulgide were specifically-designed to enhance the effi-
from a racemate (by asymmetric photoresolution or photolysis) ciency of the photoresolution process.58
or from rapidly interconverting chiral conformations (by asym- Kagan et al. pioneered the field of asymmetric photosynth-
metric photosynthesis).176–178 Asymmetric photolysis is based esis with CPL in 1971, through examining hexahelicene photo-
on the irreversible photochemical consumption of one enantio- cyclization in the presence of iodine.184 The following year,
mer at a higher rate, within a racemic mixture which does not Calvin et al. reported an e.e. of up to 2% for an octahelicene
racemize during the process (Fig. 6a). In most cases, the produced under similar conditions.185 Enantioenrichment by
(enantio-enriched) photo products are not identified. Thereby, photoresolution and photosynthesis with CPL is limited in
the enantioenrichment comes from the accumulation of the scope, since it requires molecules with high g values to be
slowly reacting enantiomer. It depends both on the unequal detected, and in intensity, since it is limited to g/2.
molar extinction coefficients (eR and eS) for CPL of the (R)- and Since its discovery by Kuhn et al. ninety years ago,186,187
(S)-enantiomers, governing the different rate constants, as well through the enantioselective decomposition of ethyl-a-bromo-
as the extent of reaction x. Asymmetric photoresolution occurs propionate and N,N-dimethyl-a-azidopropionamide, the asym-
within a mixture of enantiomers that interconvert in their metric photolysis of racemates has attracted a lot of interest.
excited states (Fig. 6b). Since the reverse reactions, from the In the common case of two competitive pseudo-first order
excited to the ground states, should not be enantiodifferentiating, photolytic reactions with unequal rate constants, kS and kR,
the deviation from the racemic mixture is only due to the for the (S) and (R) enantiomers, respectively, and if the aniso-
difference of extinction coefficients (eR and eS). While the total tropies are close to zero, the enantiomeric excess induced by

Fig. 6 Simplified kinetic schemes for asymmetric (a) photolysis, (b) photoresolution and (c) photosynthesis with CPL. SR and SS are substrate
enantiomers and SR and SS are their photoexcited states. PR and PS are the products generated from the respective photoexcited states. The thick
line represents the preferential absorption of CPL by one of the enantiomers. [SS] 4 [SR] for asymmetric photolysis and photoresolution processes whilst
[PR] 4 [PS] for asymmetric photosynthesis.

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asymmetric photolysis can be approximated as eqn (2):188 Important studies in the context of BH reported the direct
g! formation of enantio-enriched amino acids generated from
simple chemical precursors, when illuminated with CPL. Takano
e:e:  1  ð1  xÞ2  100ð%Þ (2)
et al. showed in 2007 that eleven amino acids could be generated
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

upon CPL irradiation of macromolecular compounds, originating

where x is the extent of reaction. from proton-irradiated gaseous mixtures of CO, NH3 and H2O.203
In 1974, the asymmetric photodecomposition of racemic Small e.e. values of +0.44  0.31% and 0.65  0.23% were
camphor reported by Kagan et al. reached 20% e.e. at 99% detected for alanine upon irradiation with r- and l-CPL, respec-
completion, a long-lasting record in this domain.189 Three years tively. Nuevo et al. irradiated interstellar ice analogues composed
later, Norden190 and Bonner et al.191 independently showed that of H2O, 13CH3OH and NH3 at 80 K with CPL centred at 187 nm,
enantioselective photolysis by UV-CPL was a viable source of which led to the formation of alanine with an e.e. of 1.34 
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symmetry-breaking for amino acids, by inducing an e.e. of up to 0.40%.204 The same team also studied the effect of CPL on regular
2% in aqueous solutions of alanine and glutamic acid,191 or ice analogues or organic residues coming from their irradiation in
0.2% with leucine.190 Leucine was then intensively studied order to mimic the different stages of asymmetric induction in
thanks to a relatively high anisotropy factor in the UV interstellar ices.205 Sixteen amino acids were identified, and five of
region.192 The e.e. was increased up to 1.3% in 2001 (x = 0.55) them (including alanine and valine) were analysed by enantio-
by Inoue et al. by exploiting the pH-dependence of the g selective two-dimensional gas chromatography, GC  GC,206
value.193,194 In the early 2000s, Meierhenrich et al. got closer coupled to TOF mass spectrometry, to show enantioenrichments
to astrophysically relevant conditions by irradiating samples in of up to 2.54  0.28% e.e. Optical activities likely originated from
the solid state with synchrotron vacuum ultraviolet (VUV)-CPL the asymmetric photolysis of the amino acids initially formed
(below 200 nm). This made it possible to avoid water absorp- as racemates. Advantageously, all five amino acids exhibited e.e.
tion in the VUV, and allowed electronic transitions having values of identical sign for a given polarization and wavelength,
higher anisotropy factors to be reached (Fig. 7).195 In 2005, a suggesting that irradiation by CPL could constitute a general route
solid racemate of leucine was reported to reach 2.6% of e.e. towards amino acids with a single chirality. Even though the
after illumination with r-CPL at 182 nm (x not reported).196 chiral biases generated upon CPL irradiation are modest, these
More recently, the same team improved the selectivity of the values can be significantly amplified through different physico-
photolysis process, thanks to amorphous samples of finely- chemical processes, notably those including auto-catalytic path-
tuned thickness, providing e.e. values of 5.2  0.5% and 4.2  ways (see Parts 4 and 5).
0.2% for leucine,197 and alanine,198,199 respectively. A similar (b) Spin-polarized particles. In the cosmic scenario, it is
enantioenrichment was reached in 2014 with gaseous photo- believed that the action of polarized quantum radiation in
ionized alanine,200 which constitutes an appealing result taking space, such as circularly polarized photons or spin-polarized
into account the detection of interstellar gases such as propy- particles, may have induced asymmetric conditions in the
lene oxide201 and glycine202 in star-forming regions. primitive interstellar media resulting in terrestrial bioorganic
homochirality. In particular, nuclear-decay- or cosmic-ray-
derived leptons (i.e. electrons, muons, and neutrinos) in nature
have a specified helicity, that is, they have a spin angular
momentum polarized parallel or antiparallel to their kinetic
momentum due to parity violation (PV) in the weak interaction
(Part 2).
Of the leptons, electrons are one of the most universally
present particles in ordinary materials. Spin-polarized electrons
in nature are emitted with b decay from radioactive nuclear
particles derived from PV involving the weak nuclear inter-
action and spin-polarized positrons (the anti-particle of elec-
trons) from b+ decay. In b/b+-decay, with weak interaction, the
spin angular momentum vectors of electrons/positrons are
perfectly polarized as antiparallel/parallel to the vector direc-
tion of the kinetic momentum. In this meaning, spin-polarized
electrons/positrons are ‘‘chiral radiation’’, as well as are muons
Fig. 7 Anisotropy spectra (thick lines, left ordinate) of isotropic amor- and neutrinos, which will be mentioned below. It is expected
phous (R)-alanine (red) and (S)-alanine (blue), in the VUV and UV spectral that spin-polarized leptons will induce reactions different from
regions. Dashed lines represent the enantiomeric excess (right ordinate) those triggered by CPL. For example, b decay from 60Co is
that can be induced by photolysis of rac-alanine with either left- (in red) or
accompanied by circularly polarized gamma-rays.207 Similarly,
right- (in blue) circularly polarized light at x = 0.9999. Positive e.e. values
correspond to scalemic mixture biased in favour of (S)-alanine. Note that
spin-polarized muon irradiation has the potential to induce
enantiomeric excesses are calculated from eqn (2). Reprinted from ref. 192 novel types of optical activities different from those of polarized
with permission from Wiley-VCH, copyright 2017. photon and spin-polarized electron irradiation.

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Single-handed polarized particles produced by supernovae

explosions may thus interact with molecules in the proto-solar
clouds.35,207–210 Left-handed electrons generated by b-decay
impinge on matter to form a polarized electromagnetic radia-
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

tion through bremsstrahlung. At the end of fifties, Vester and

Ulbricht suggested that these circularly-polarized ‘‘Bremsstrahlen’’
photons can induce and direct asymmetric processes towards a
single direction upon interaction with organic molecules.107,211
From the sixties to the eighties,212–220 many experimental
attempts to show the validity of the ‘‘V–U hypothesis’’, generally
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by photolysis of amino acids in the presence of a number

of b-emitting radionuclides or through self-irradiation of
14
C-labeled amino acids, only led to poorly conclusive
results.44,221,222 During the same period, the direct effect of Fig. 8 Enantioselective dissociation of epichlorohydrin by spin polarized
high-energy spin-polarized particles (electrons, protons, posi- SEs. Red (black) arrows indicate the electron’s spin (motion direction,
trons and muons) has been probed for the selective destruction respectively). Reprinted from ref. 229 with permission from Wiley-VCH,
copyright 2015.
of one amino acid enantiomer in a racemate, but without
further success as reviewed by Bonner.44,54 More recent inves-
tigations by the international collaboration RAMBAS (RAdiation
Mechanism of Biomolecular ASymmetry) claimed minute e.e. a difference of about ten percent in the rate of CO bond cleavage
values (up to 0.005%) upon irradiation of various amino acid of the enantiomers. Extrapolations of the experimental results
racemates with (natural) left-handed electrons.223,224 suggested that an e.e. of 25% would be obtained after photolysis
Other fundamental particles have been proposed to play a of the racemate at 98.6% of conversion. Importantly, the different
key role in the emergence of BH.207,209,225 Amongst them, electron rates in the photolysis of the 2-butanol enantiomers depend on
antineutrinos have received particular attention, through the spin polarization of SEs, showing the first example of
the Supernova Neutrino Amino Acid Processing (SNAAP) CISS.232–234 Later, SEs with a higher degree of spin polarization
model.226–228 Electron antineutrinos are emitted after a super- (60%) were found to dissociate Cl from epichlorohydrin (Epi) with
nova explosion, to cool the nascent neutron star, and, by a a quantum yield 16% greater for the S form.229 To achieve this,
similar reasoning to that applied with neutrinos, they are all electrons are produced by X-ray irradiation of a gold substrate and
right-handed. According to the SNAAP scenario, right-handed spin-filtered by a self-assembled overlayer of DNA before they
electron antineutrinos generated in the vicinity of neutron stars reach the adlayer of Epi (Fig. 8).
with strong magnetic and electric fields were presumed to In 2018, Banerjee-Ghosh et al. showed that a magnetic field
selectively transform 14N into 14C, and this process depended perpendicular to a ferromagnetic (FM) substrate can gene-
on whether the spin of 14N was aligned or anti-aligned with that rate enantioselective adsorption of polyalanine, ds-DNA and
of the antineutrinos. Calculations predicted enantiomeric cysteine.235 One enantiomer was found to be more rapidly
excesses for amino acids from 0.02% to a few percent, and a adsorbed on the surface depending on the magnetization
preferential enrichment in (S)-amino acids. direction (Fig. 9). The effect is not attributed to the magnetic
Despite important efforts, no experimental evidence has field per se but to the exchange interaction between the
been reported to date in favour of a deterministic scenario for adsorbed molecules and surface electron spins, i.e. CISS.
the generation of a chiral bias in prebiotic molecules. Enantioselective crystallization of initially racemic mixtures
(c) Chirality induced spin selectivity (CISS). An electron in of asparagine, glutamic acid, and threonine, known to crystal-
helical roto-translational motion with spin–orbit coupling lize as conglomerates, was also observed on a ferromagnetic
(i.e. translating in a ‘‘ballistic’’ motion with its spin projection substrate surface (Ni(120 nm)/Au(10 nm)).230 The racemic
parallel or antiparallel to the direction of propagation) can be mixtures were crystallized from aqueous solution on the ferro-
regarded as chiral, existing as two possible enantiomers, magnetic surfaces in the presence of two magnets, one pointing
corresponding to the a and b spin configurations, which do north and the other south, located at different sites of
not coincide upon space and time inversion. Such peculiar the surface. A clear enantioselective effect was observed in the
‘‘chiral actor’’ is the object of spintronics, the fascinating field formation of an excess of D- or L-crystals, depending on the
of modern physics which deals with the active manipulation of direction of the magnetization orientation.
spin degrees of freedom of charge carriers.230 The interaction In 2020, the CISS effect was successfully applied to several
between polarized spins of secondary electrons (SEs) and chiral asymmetric chemical processes, SEs acting as chiral reagents.236
molecules leads to chirality induced spin selectivity (CISS), Spin-polarized electrons, produced by a magnetized Ni/Au sub-
a recently reported phenomenon. strate coated with an achiral self-assembled monolayer (SAM)
In 2008, Rosenberg et al.231 irradiated adsorbed molecules of carboxyl-terminated alkanethiols [HS–(CH2)x1–COO],
of (R)-2-butanol or (S)-2-butanol on a magnetized iron substrate caused an enantiospecific association of 1-amino-2-propanol
with low-energy SEs (10–15% of spin polarization) and measured enantiomers, leading to an e.e. of 20% in the reactive medium.

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assuming that only one enantiomer can present three groups

that match three active positions of the chiral surface,243 fails
to fully explain chiral recognition which are the fruit of more
subtle interactions.244 In the second part of the XXth century,
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

a large number of studies have focused on demonstrating

chiral interactions between biological molecules and inorganic
mineral surfaces.
Quartz is the only common mineral which is composed of
Fig. 9 Suggested mechanism for the enantiospecific interaction triggered enantiomorphic crystals. Right-handed (D-quartz) and left-
by chiral-induced spin selectivity. Enantiomers are sketched as opposite handed (L-quartz) can be separated (similarly to the tartaric
green helices and electrons as orange spheres with straight arrows
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acid salts of the famous Pasteur experiment) and investigated

indicating their spin orientation, which can be reversed for surface
electrons by changing the magnetization direction. In contact with the
independently in adsorption studies of organic molecules. The
perpendicularly magnetized FM surface, molecular electrons are redis- process of separation is made somewhat difficult by the
tributed to form a dipole, and the spin orientation at each pole depends on presence of ‘‘Brazilian twins’’ (also called chiral or optical
the chiral potentials of enantiomers. The interaction between the FM twins),242 which might bias the interpretation of the experi-
substrate and the adsorbed molecule (blue arrows) is favoured when the ments. Bonner et al. in 1974245,246 measured the differential
two spins are antiparallel leading to the preferential adsorption of one
enantiomer over the other. Reprinted from ref. 230 with permission from
adsorption of alanine derivatives defined as % adsorbed on
the Royal Society of Chemistry, copyright 2019, under Creative Commons D-quartz – % adsorbed on L-quartz. These authors reported on
Attribution 3.0 Unported License https://creativecommons.org/licenses/ the small but significant 1.4  0.4% preferential adsorption
by/3.0/. of (R)-alanine over D-quartz and (S)-alanine over L-quartz,
respectively. A more precise evaluation of the selectivity with
radiolabelled (RS)-alanine hydrochloride led to higher levels of
The enantioselective electro-reduction of (1R/1S)-10-camphor- differential adsorption between L-quartz and D-quartz (up to
sulfonic acid (CSA) into isoborneol was also governed by the 20%).247 The hydrochloride salt of alanine isopropyl ester was
spin orientation of SEs, injected through an electrode, with an also found to be adsorbed enantiospecifically from its chloro-
e.e. of about 11.5% after the electrolysis of 80% of the initial form solution leading to chiral enrichment varying between
amount of CSA. 1.5 and 12.4%.248 Furuyama and co-workers also found prefer-
Electrochirogenesis links the CISS process to biological ential adsorption of (S)-alanine and (S)-alanine hydrochloride
homochirality through several theories, all based on an initial over L-quartz from their ethanol solutions.249,250 Anhydrous
bias stemming from spin polarized electrons.232,237 Strong conditions are required to get sufficient adsorption of the
fields and radiations of neutron stars could align ferrous organic molecules onto a-quartz crystals which, according to
magnetic domains in interstellar dust particles, and produce Bonner, discards a-quartz as a suitable mineral for the derace-
spin-polarized electrons, able to create an enantiomeric excess mization of building blocks of life.251 According to Hazen and
into adsorbed chiral molecules. One enantiomer from a race- Scholl,239 the fact that these studies have been conducted on
mate in a cosmic cloud would merely accrete on a magnetized powdered quartz crystals (i.e. polycrystalline quartz) has ham-
domain in an enantioselective manner as well. Alternatively, pered a precise determination of the mechanism and magni-
magnetic minerals of the prebiotic world, like pyrite (FeS2) tude of adsorption on specific surfaces of a-quartz. Some of the
or greigite (Fe3S4), might serve as an electrode in the asym- faces of quartz crystals likely display opposite chiral prefer-
metric electrosynthesis of amino acids or purines, or as a spin ences which may have reduced the experimentally-reported
filter in the presence of an external magnetic field, e.g. in chiral selectivity. Moreover, chiral indices of the commonest
hydrothermal vents. crystal growth surfaces of quartz, as established by Downs and
Hazen, are relatively low (or zero), suggesting that the potential
3.3 Chiral surfaces of enantiodiscrimination of organic molecules by quartz is
(a) Inorganic minerals and clays. Chiral surfaces constitute weak in overall.252 Quantum-mechanical studies using density
unequivocal true asymmetry sources that are widespread over functional theories (DFT) have also been performed to probe
the earth surface in the form of various minerals, a-quartz, the enantiospecific adsorption of various amino acids on
calcite, gypsum, and some clays notably. The implication of hydroxylated quartz surfaces.253–256 In short, the computed
chiral surfaces in the context of BH has been debated44,238–242 differences in the adsorption energies of the enantiomers are
along two main axes: (i) the preferential adsorption of pre- modest (on the order of 2 kcal mol1 at best) but strongly
biotically relevant molecules, and (ii) the potential unequal depend on the nature of amino acids and quartz surfaces.
distribution of left-handed and right-handed surfaces for a A final argument against the implication of quartz as a deter-
given mineral or clay on the earth surface. ministic source of chiral discrimination of the molecules of life
Selective adsorption is generally the consequence of rever- comes from the fact that D-quartz and L-quartz are equally
sible and preferential diastereomeric interactions between distributed on earth.257,258
the chiral surface and one of the enantiomers,239 commonly Calcite (CaCO3), as the most abundant marine mineral in
described by the simple three-point model. But this model, the Archaean era, has potentially played an important role in

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the formation of prebiotic molecules relevant to life. The crystal structure.265 As expected, asymmetric morphologies pro-
trigonal scalenohedral crystal form of calcite displays chiral duced from amino acid enantiomers are mirror image (Fig. 10).
faces which can yield chiral selectivity. In 2001, Hazen et al.261 Clay minerals, of which some of them display high specific
reported that (S)-aspartic acid adsorbs preferentially on the surface area, and adsorption and catalytic properties, are often
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

(31% 2% 1) face of calcite, whereas (R)-aspartic acid adsorbs prefer- invoked as potential promoters of the transformation of
entially on the (213% 1) face. An e.e. value in the order of prebiotic molecules. Amongst the large variety of clays, serpen-
0.5% on average was measured for the adsorbed aspartic acid tine and montmorillonite were likely the dominant ones on
molecules. No selectivity was observed on a centric surface earth prior to life’s origin.241 Clay minerals can exhibit non-
that served as control. The experiments were conducted with centrosymmetric structures, such as the A and B forms of
aqueous solutions of (rac)-aspartic acid and selectivity was kaolinite, which correspond to the enantiomeric arrangement
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greater on crystals with terraced surface textures, presumably of the interlayer space. These chiral organizations are, however,
because enantiomers concentrated along step-like linear growth not individually separable. All experimental studies claiming
features. The calculated chiral indices of the (214) scalenohedral asymmetric inductions by clay minerals reported in the literature
face of calcite was found to be the highest amongst 14 surfaces have raised suspicion about their validity, with no exception.242
selected from various minerals (calcite, diopside, quartz, and This is because these studies employed either a racemic clay or
orthoclase) and face-centred cubic (FCC) metals.252 In contrast, clays which have no established chiral arrangement, i.e. presum-
DFT studies revealed negligible difference in adsorption ener- ably achiral clay minerals. Asymmetric adsorption and polymer-
gies of enantiomers (o1 kcal mol1) of alanine on the (213% 1) ization of amino acids reported with kaolinite266–270 and
face of calcite because alanine cannot establish three points of bentonite271–273 in the 1970s–1980s actually originated from
contact on the surface.262 Conversely, it is well established that experimental errors or contaminations. Supposedly enantiospeci-
amino acids modify the crystal growth of calcite crystals in fic adsorptions of amino acids with allophane,274 hydrotalcite-like
a selective manner leading to asymmetric morphologies, e.g. compound,275 montmorillonite,276 and vermiculite277,278 also
upon crystallization263,264 or electrodeposition (Fig. 10a).259 likely belong to this category.
Vaterite helicoids, produced by crystallization of CaCO3 in Experiments aimed at demonstrating deracemization of
the presence of non-racemic mixtures of aspartic acid, were amino acids in the absence of any chiral inducers or during
found to be single-handed (Fig. 10b).260 Enantiomeric ratio are phase transition under equilibrium conditions have to be
identical in the helicoids and in solution, i.e. incorporation interpreted cautiously (see the Chapter 4.2 of the book written
of aspartic acid in valerite displays no chiral amplification by Meierhenrich for a more comprehensive discussion on
effect. Asymmetric growth was also observed for various organic this topic).24 Deracemization is possible under far-from-
substances with gypsum, another mineral with a centrosymmetric equilibrium conditions but a set of repeated experiments must
then reveal a distribution of the chiral biases (see Part 4). The
claimed specific adsorptions for racemic mixtures of amino
acids likely originated from the different purities between
(S)- and (R)-amino acids; or contaminants of biological origin
such as microbial spores.279 Such issues are not old-fashioned
and despite great improvement in analytical and purification
techniques, the difference in enantiomer purities is most likely
at the origin of the different behaviour of amino acid enantio-
mers observed in the crystallization of wulfingite (e-Zn(OH)2)280
and CaCO3281,282 in two recent reports.
Very impressive levels of selectivity (on the range of 10% e.e.)
were recently reported for the adsorption of aspartic acid on
brushite, a mineral composed of achiral crystals of CaHPO4
2H2O.283 In this case, selective adsorption was observed under
supersaturation and undersaturation conditions (i.e. non-
equilibrium states) but not at saturation (equilibrium state).
Likewise, opposite selectivity was observed for the two non-
Fig. 10 Asymmetric morphologies of CaCO3-based crystals induced by
equilibrium states. It was postulated that mirror symmetry
enantiopure amino acids. (a) Scanning electron micrographs (SEM) of
calcite crystals obtained by electrodeposition from calcium bicarbonate
breaking of the crystal facets occurred during the dynamic
in the presence of magnesium and (S)-aspartic acid (left), and (R)-aspartic events of crystal growth and dissolution. Spontaneous mirror
acid (right). Reproduced with permission from ref. 259. Copyright 2007. symmetry breaking is not impossible under far-from-
American Chemical Society. (b) SEM images of vaterite helicoids obtained equilibrium conditions but again a distribution of the selectiv-
by crystallization in the presence of non-racemic solutions (40% e.e.)
ity outcome is expected upon repeating the experiments under
biased in favour of (S)-aspartic acid (left) and (R)-aspartic acid (right).
Reprinted from ref. 260. Copyright 2019. Springer Nature under Creative
strictly achiral conditions (Part 4).
Commons Attribution 4.0 International License https://creativecommons. Ribó and co-workers proposed that chiral surfaces could
org/licenses/by/4.0/. have been involved in the chiral enrichment of prebiotic

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molecules on carbonaceous chondrites present on meteorites.284

In their scenario, mirror symmetry breaking during the formation
of planetesimal bodies and comets may have led to a bias in the
distribution of chiral fractures, screw distortions or step-kink
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

chiral centres on the surfaces of these inorganic matrices. This

in turn would have led to a bias in the adsorption of organic
compounds. Their study was motivated by the fact that the
enantiomeric excesses measured for organic molecules vary
according to their location on the meteorite surface.285 Their
measurement of the optical activity of three meteorite samples
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by circular birefringence (CB) indeed revealed a slight bias

towards negative CB values for the Murchinson meteorite.
The optically active areas are attributed to serpentines and
other poorly identified phyllosilicate phases, whose formation
may have occurred concomitantly to organic matter.
The implication of inorganic minerals in biasing the chir-
ality of prebiotic molecules remains uncertain given that no
strong asymmetric adsorption values have been reported to
date and that certain minerals were even found to promote the
racemization of amino acids286 and secondary alcohols.287
However, evidence exists that minerals could have served as
hosts and catalysts for prebiotic reactions, including the poly- Fig. 11 Resolution of amino acid enantiomers following a ‘‘by chance’’
merization of nucleotides.288 In addition, minute chiral biases mechanism including enantioselective occlusion into achiral crystals of
provided by inorganic minerals could have driven SMSB glycine.289,290
processes into a deterministic outcome (Part 4).
(b) Organic crystals. Organic crystals may have also played
a role in biasing the chirality of prebiotic chemical mixtures. A somewhat related strategy was disclosed in 2010 by Soai
Along this line, glycine appears as the most plausible candidate and co-workers.292 Dehydration of centrosymmetric crystals of
given its probable dominance over more complex molecules in cytosine monohydrate yielded enantio-enriched anhydrous
the prebiotic soup. cytosine chiral crystals when only one of two enantiotopic faces
a-Glycine crystallizes from water into a centrosymmetric of the crystal was put into direct contact with the hot plate.
form. In the 1980s, Lahav, Leiserowitch and co-workers demon- Enrichment was also observed if the dehydration was per-
strated that amino acids were occluded to the basal faces formed under reduced pressure but with a surprising inversion
(010 and 01% 0) of glycine crystals with exquisite selectivity.289–291 of the configuration of the chiral crystal relative to thermal
For example, when a racemic mixture of leucine (1–2% wt/wt of dehydration.293 Rearrangement of the hydrogen bond network
glycine) was crystallized with glycine at an air/water interface, during transition between the centrosymmetric and chiral
(R)-Leu was incorporated only into those floating glycine forms of the cytosine crystals is likely at the origin of this
crystals whose (010) faces were exposed to the water solution, selective process. Reactions occurring at the enantiotopic surface
while (S)-Leu was incorporated only into the crystals with of an organic crystal also yields enantio-enriched compounds
exposed (01% 0) faces. This results in the nearly perfect resolution whose optical purity can be enhanced by SMSB processes.294,295
(97–98% e.e.) of Leu enantiomers. In the presence of a small (c) Metal surfaces. The last two decades have seen the
amount of an enantiopure amino-acid (e.g. (S)-Leu), all crystals emergence of chiral metal surfaces displaying high adsorption
of Gly exposed the same face to the water solution leading enantioselectivities.239,244,296 The choice between metal sur-
to one enantiomer of a racemate being occluded in glycine faces can be oriented based on computational predictions of
crystals while the other remains in solution. These striking their enantiospecificity as reported recently for a variety of
observations led the same authors to propose a scenario in a-amino acids on Ag/Cu/Pd/Pt(531) surfaces.297 Mechanisms
which the crystallization of supersaturated solutions of glycine leading to specific adsorptions on chiral metal surfaces can be
in the presence of amino-acid racemates would have led to the well established. For example, the decomposition of tartaric
spontaneous resolution of all amino acids (Fig. 11). acid, enantiospecifically adsorbed on Cu(651)S surfaces, follows
This can be considered as a ‘‘by chance’’ mechanism in non-linear kinetics, suggesting auto-catalysis.298 Likewise,
which one of the enantiotopic face (010) would have been adsorption of scalemic mixtures of aspartic acid onto an achiral
exposed preferentially to the solution in the absence of any Cu(111) surface occurs with amplification of chirality, i.e. the
chiral bias. From then, the solution, enriched into (S)-amino e.e. of the adsorbed enantiomers of the surface is largely higher
acids, enforces all glycine crystals to expose their (010) faces to than the e.e. of enantiomers in the gas phase.299 This effect,
water, eventually leading to all (R)-amino acids being occluded which presents some similarity to non-linear effects observed
in glycine crystals. in asymmetric catalysis,62 is related to the formation of

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homochiral adsorbate clusters. Auto-catalysis and chiral ampli-

fication are two key requirements for spontaneous mirror
symmetry breaking (Part 4) and consequently such mechanistic
studies on chiral metal surfaces may reveal important pathways
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towards homochirality.300

4. Spontaneous mirror-symmetry
breaking (SMSB)
4.1 Definition, models and the Soai reaction
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Spontaneous mirror-symmetry breaking (SMSB) phenomenon

is the process that leads to the preferential formation of one
chiral state over its enantiomeric form in the absence of a
detectable chiral bias or enantiomeric imbalance. As defined by
Ribó and co-workers, SMSB concerns the transformation of
Fig. 12 (a) General scheme for an auto-catalysed asymmetric reaction.
‘‘metastable racemic non-equilibrium stationary states (NESS) (b) The Soai reaction performed in the presence of detected chirality,
into one of two degenerate but stable enantiomeric NESSs’’.301 leading to highly enantio-enriched alcohol with the same configuration in
Although this definition is somewhat in contradiction with the successive experiments (deterministic SMSB). (c) Soai reaction performed
textbook statement that enantiomers need the presence of a in the absence of detected chirality, leading to highly enantio-enriched
alcohol with a bimodal distribution of the configurations in successive
chiral bias to be distinguished, it was recognized a long time
experiments (stochastic SMSB).
ago that SMSB can emerge from reactions involving asymmetric
self-replication or auto-catalysis. The connection between
SMSB and BH is appealing,25,40,51,301–308 since SMSB is the extremely weak chiral perturbations: quartz, cryptochiral mole-
unique physicochemical process that allows for the emergence cules, circularly polarized light, and chiral isotopomers amongst
and retention of enantiopurity from scratch. It is also intriguing others (Fig. 12b).312 In addition, the apparent outcome of the
to note that the competitive chiral reaction networks that might Soai reaction performed in the absence of detectable chiral
give rise to SMSB could exhibit replication, dissipation and species is stochastic as expected for a truly SMSB process
compartmentalization,301,309 i.e. fundamental functions of liv- (Fig. 12c).325–333 On the one hand, the Soai reaction offers a
ing systems. credible mechanistic scenario from which homochiral bio-
Systems able to lead to SMSB consist of enantioselective molecules at the origin of life would have been created on a
autocatalytic reaction networks, described through models deterministic manner through a SMSB process coupled to an
dealing with either the transformation of achiral to chiral infinitesimal chiral bias (vide infra). This bias would have
compounds, or the deracemization of racemic mixtures.301 survived from a larger one despite significant erosion through
As early as 1953, Frank described a theoretical model dealing racemization processes. On the other hand, the Soai reaction is
with the former case. According to Frank’s model, SMSB more an exception than a rule in the chemical space explored to
emerges from a system involving homochiral self-replication date.334–342 The exergonic and irreversible nature of the organo-
(one enantiomer of the chiral product accelerates its own zinc addition reaction are key for pushing the system far-from-
formation) and heterochiral inhibition (the replication of equilibrium and for the generation and preservation of the
the other product enantiomer is prevented).303 It is now well- homochiral state. On the contrary, it is assumed that prebiotic
recognized that the Soai reaction,56 an auto-catalytic asym- chemical reactions would have been only weakly exergonic,
metric process (Fig. 12a), disclosed 42 years later,310 is an i.e. their products would have been more prone to racemization
experimental validation of the Frank model. The reaction or to side reactions occurring in solution.37,46,301
between pyrimidine-5-carbaldehyde and diisopropyl zinc (two Many other models of spontaneous emergence of homo-
achiral reagents) is strongly accelerated by their zinc alkoxy chirality in far-from-equilibrium systems have been proposed
product, which is found to be enantiopure (499% e.e.) after a in the literature.343–345 Most of them are derived from the Frank
few cycles of reaction/addition of reagents (Fig. 12b and c).310–312 model but do not include any mutual inhibition reaction. The
Kinetic models based on the stochastic formation of homochiral limited enantioselective (LES) model306,346 assumes that both
and heterochiral dimers313–315 of the zinc alkoxy product provide the asymmetric auto-catalysis (similar to the homochiral self-
good fits of the kinetic profile even though the involvement of replication in the Frank model) and the non-enantioselective
higher species has gained more evidence recently.316–324 In this auto-catalysis (the accelerated formation of both enantiomers
model, homochiral dimers serve as auto-catalysts for the for- of the product) can co-exist. SMSB emerges if these two auto-
mation of the same enantiomer of the product whilst hetero- catalytic processes are (i) individually compartmentalized
chiral dimers are inactive and sequester the minor enantiomer, a within regions experiencing different temperatures,347,348 or
Frank model-like inhibition mechanism. A hallmark of the Soai (ii) driven by a constant concentration of external reagents.349
reaction is that the direction of auto-catalysis is dictated by Required conditions for SMSB through the LES model could

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have been present in deep ocean hydrothermal plumes. Likewise,

a chemical scenario has been proposed for LES based on coupled
Strecker-type reactions for amino acid synthesis and degradation
which have been postulated to be accelerated by a heterogeneous
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catalytic support such as phyllosilicates.349 However, the LES

model has found no experimental evidence to date. Models for
enantioselective hypercyclic replicators were recently disclosed
in which the inhibition reaction in the Frank model has been Fig. 13 Enantiomeric preferential crystallization of N,N,N-allylethyl-
replaced by mutual cross-catalytic processes occurring between methylanilinium iodide as described by Havinga. Fast racemization in
solution supplies the growing crystal with the appropriate enantiomer.
families of coupled replicators.350,351 These models support a
Adapted from ref. 55 with permission from the Royal Society of Chemistry,
Open Access Article. Published on 04 April 2022. Downloaded on 6/14/2025 12:35:37 PM.

scenario in which the combination of SMSB, formation of the first copyright 2015.
(coupled) self-replicators and the emergence of their functions
would have led to BH.301 This intriguing concept may foster
experimental investigations of SMSB processes in polymeriza- one year. Crystallization occurred upon further cooling: three
tion/depolymerization reactions. crystalline products with no optical activity were obtained,
Imposed boundary conditions for SMSB involve ‘‘either while the other four showed a small optical activity ([a]D =
systems open to matter exchange, or closed systems unable to +0.21; +0.71; 0.51; 3.01). More successful examples of prefer-
equilibrate energy with their surroundings’’.301 In the absence ential crystallization of one enantiomer appeared in the litera-
of any chiral influence, the obtained metastable NESSs are ture notably with tri-o-thymotide,356 and 1,1 0 -binaphthyl.357,358
exposed to statistical fluctuations, and evolve towards scalemic In the latter case, the distribution of specific rotations recorded
or homochiral NESSs, as long as the systems are far-from- for several independent experiments is centred to zero.
equilibrium. It is important to note that in the absence of Sodium chlorate (NaClO3) crystallizes by evaporation of
these boundary conditions, systems will be able to equilibrate water into a conglomerate (P213 space group).359–361 Preferen-
with their surrounding and the deviation from the racemic tial crystallization of one of the crystal enantiomorph over the
state will be lost, e.g. racemization would occur under classi- other was already reported by Kipping and Pope in 1898.362,363
cally employed reaction workups operated in solution.41,352 From static (i.e. non-stirred) solution, NaClO3 crystallization
This is probably the main reason why a single SMSB process seems to undergo an uncertain resolution, similar to Havinga’s
has been identified to date for a reaction performed in solution findings with the aforementioned quaternary ammonium salt.
(the Soai reaction). On the contrary, SMSB processes have been However, a statistically significant bias in favour of D-crystals
observed more frequently in crystals (vide infra) or in supra- was invariably observed, likely due to the presence of bio-
molecular assemblies,353 i.e. processes involving phase transition. contaminants.364 Interestingly, Kondepudi et al. showed in
Asymmetric reactions performed with catalytic single-handed 1990 that magnetic stirring, during the crystallization of
supramolecular assemblies obtained through a SMSB process sodium chlorate, randomly oriented the crystallization to only
were found to yield enantio-enriched products whose configu- one enantiomorph, with a virtually perfect bimodal distribution
ration is left to chance.157,354 SMSB processes leading to over several samples (1).365 Further studies366–369 revealed
homochiral crystals as the final state appear particularly rele- that the maximum degree of supersaturation is solely reached
vant in the context of BH and will thus be discussed separately once, when the first primary nucleation occurs. At this stage,
in the following section. the magnetic stirring bar breaks up the first nucleated crystal
into small fragments that have the same chirality than the
4.2 Homochirality by crystallization ‘Eve crystal’, and act as secondary nucleation centres whence
Havinga postulated that just one enantiomorph can be crystals grow (Fig. 14). This constitutes a SMSB process cou-
obtained upon a gentle cooling of a racemate solution (i) when pling homochiral self-replication plus inhibition through the
the crystal nucleation is rare and the growth is rapid and supersaturation drop during secondary nucleation, precluding
(ii) when fast inversion of configuration occurs in solution new primary nucleation and the formation of crystals of the
(i.e. racemization). Under these circumstances, only monomers mirror-image form.307 This deracemization strategy was also
with matching chirality to the primary nuclei crystallize leading successfully applied to 4,4 0 -dimethyl-chalcone,370 and 1,1 0 -bi-
to SMSB.55,355 Havinga reported in 1954 a set of experiments naphthyl (from its melt).371
aimed at demonstrating his hypothesis with N,N,N-allyl- In 2005, Viedma reported that solid-to-solid deracemization
ethylmethylanilinium iodide – an organic molecule which of NaClO3 proceeded from its saturated solution by abrasive
crystallizes as a conglomerate from chloroform (Fig. 13).355 grinding with glass beads.373 Complete homochirality with
Fourteen supersaturated solutions were gently heated in sealed bimodal distribution is reached after several hours or days.374
tubes, then stored at 0 1C to give crystals which were in 12 cases The process can also be triggered by replacing grinding with
inexplicably more dextrorotatory (measurement of optical activ- ultrasound,375 turbulent flow,376 or temperature variations.376,377
ity by dissolution in water, where racemization is not observed). Although this deracemization process is easy to implement, the
Seven other supersaturated solutions were carefully filtered mechanism by which SMSB emerges is an ongoing highly topical
before cooling to 0 1C, but no crystallization occurred after question that falls outside the scope of this review.40,41,378–381

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ripening, albeit with a stochastic distribution of the optical

activities.390 Salts or imine derivatives of alanine,391,392
phenylglycine372,384 and phenylalanine391,393 were desym-
metrized by Viedma ripening with DBU (1,8-diazabicyclo-
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

[5.4.0]undec-7-ene) as the racemization catalyst. Successful

deracemization was also achieved with amino acid precursors
such as a-aminonitriles,394–396 a-iminonitriles,397 N-succino-
pyridine398 and thiohydantoins.399 The first three classes of
compounds could be obtained directly from prochiral precur-
Fig. 14 Primary nucleation of an enantiopure ‘Eve crystal’ of random
sors by coupling synthetic reactions and Viedma ripening.
chirality, slightly amplified by growing under static conditions (top,
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Havinga-like), or strongly amplified by secondary nucleation thanks to

In the preceding examples, the direction of the SMSB process
magnetic stirring (bottom, Kondepudi-like) from rapidly racemizing chiral is selected by biasing the initial racemic mixtures in favour of
molecules, (S) and (R), or achiral molecules, A. Reprinted from ref. 55 with one enantiomer or by seeding the crystallization with chiral
permission from the Royal Society of Chemistry, copyright 2015. chemical additives. In the next sections, we will consider the
possibility to drive the SMSB process towards a deterministic
outcome by means of PVED, physical fields, polarized particles,
Viedma ripening was exploited for deracemization of conglo-
and chiral surfaces, i.e. the sources of asymmetry depicted in
merate-forming achiral or chiral compounds (Fig. 15).55,382 The
Parts 2 and 3 of this review.
latter can be formed in situ by a reaction involving a prochiral
substrate. For example, Vlieg et al. coupled an attrition-enhanced 4.3 Deterministic SMSB processes
deracemization process with a reversible organic reaction (an
(a) Parity violation coupled to SMSB. In the 1980s, Konde-
aza-Michael reaction) between prochiral substrates under
pudi and Nelson constructed stochastic models of a Frank-
achiral conditions to produce an enantiopure amine.383 In a
type autocatalytic network which allowed them to probe the
recent review, Buhse and co-workers identified a range of
sensitivity of the SMSB process to very weak chiral
conglomerate-forming molecules that can be potentially dera-
influences.304,400–402 Their estimated energy values for biasing
cemized by Viedma ripening.41 Viedma ripening also proves to
the SMSB process into a single direction was in the range of
be successful with molecules crystallizing as racemic com-
PVED values calculated for biomolecules. Despite the competi-
pounds under the condition that the conglomerate form is
tion with the bias originated from random fluctuations (as
energetically accessible.384 Furthermore, a promising mechan-
underlined later by Lente),126 it appears possible that such a
ochemical method to transform racemic compounds of amino
very weak ‘‘asymmetric factor can drive the system to a pre-
acids into their corresponding conglomerates has been recently
ferred asymmetric state with high probability’’.307 Recently,
found.385 When valine, leucine and isoleucine were milled one
Blackmond and co-workers performed a series of experiments
hour in the solid state, in a Teflon jar with a zirconium ball and
with the objective of determining the energy required for over-
in the decisive presence of zinc oxide, their corresponding
coming the stochastic behaviour of well-designed Soai403 and
conglomerates eventually formed.
Viedma ripening experiments.404 This was done by performing
Shortly after the discovery of Viedma, aspartic acid386 and
the SMSB processes with very weak chiral inductors, isotopically
glutamic acid387,388 were deracemized up to the homochiral state
chiral molecules and isotopologue enantiomers for the Soai
starting from biased racemic mixtures. The chiral g-polymorph of
reaction and the Viedma ripening, respectively. The calculated
glycine389 was obtained with a preferred handedness by Ostwald
energies, 0.15 kJ mol1 (for Viedma) and 2  108 kJ mol1
(for Soai), are considerably higher than the PVED estimates
(ca. 1012–1015 kJ mol1). This indicates that the two experi-
mental SMSB processes reported to date are not sensitive
enough to detect any influence of PVED and questions the
existence of an ultra-sensitive auto-catalytic process, as the one
described by Kondepudi and Nelson.
The possibility to bias crystallization processes with chiral
particles emitted by radionuclides was probed by several groups
as summarized in the reviews of Bonner.44,54 Kondepudi-like
crystallization of NaClO3 in the presence of b particles from a
90
39Sr source notably yielded a distribution of (+) and
Fig. 15 Schematic representation of Viedma ripening and solution–solid ()-NaClO3 crystals, largely biased in favour of (+) crystals.405
equilibria of an intrinsically achiral molecule (a) and a chiral molecule It was presumed that spin polarized electrons produced
undergoing solution-phase racemization (b). The racemic mixture can
chiral nucleating sites, albeit chiral contaminants cannot be
result from chemical reaction involving prochiral starting materials (c).
Adapted from ref. 55 with permission from the Royal Society of Chemistry,
excluded.
copyright 2015 and from ref. 372. Copyright 2008. American Chemical (b) Chiral surfaces coupled to SMSB. The extreme sensitivity
Society. of the Soai reaction to chiral perturbations is not restricted to

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soluble chiral species.312 Enantio-enriched or enantiopure pyri-

midine alcohol was generated with determined configuration
when the auto-catalytic reaction was initiated with chiral crystals,
such as (a)-quartz,406 g-glycine,407 N-(2-thienylcarbonyl)glycine,408
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cinnabar,409 anhydrous cytosine,292 or triglycine sulfate,410 or with

enantiotopic faces of achiral crystals such as CaSO42H2O
(gypsum).411 Even though the selective adsorption of product to
crystal faces has been observed experimentally409 and
computed,408 the nature of the heterogeneous reaction steps that
provide the initial enantiomer bias remains to be determined.300
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The effect of chiral additives on crystallization processes, in

which the additive inhibits one of the enantiomer growth
thereby enriching the solid phase with the opposite enantiomer
is well established as ‘‘the rule of reversal’’.412,413 In the realm
of the Viedma ripening, Noorduin et al. discovered in 2020 a
way of propagating homochirality between a-iminonitriles,
possible intermediates in the Strecker synthesis of a-amino
acids.414 These authors demonstrated that an enantiopure
additive (1–20 mol%) induces an initial enantio-imbalance, Fig. 16 (a) Molecular structure of rac-1. (b) CPL-controlled complete
which is then amplified by Viedma ripening up to a complete attrition-enhanced deracemization of rac-1. (S) and (R) are the enantio-
mirror-symmetry breaking. In contrast to the ‘‘rule of reversal’’, mers of rac-1 and S* and R* are chiral photoproducts formed upon CPL
irradiation of rac-1.419
the additive favours the formation of the product with identical
configuration. The additive is actually incorporated in a ther-
modynamically controlled way into the bulk crystal lattice of controlled by a non-identified chiral photoproduct generated
the crystallized product of the same configuration, i.e. a solid upon irradiation of (rac)-1 by CPL. This photoproduct (S* or R*
solution is formed enantiospecifically. in Fig. 16b) then serves as an enantioselective crystal-growth
(c) CPL coupled to SMSB. Coupling CPL-induced enan- inhibitor which mediates the deracemization process towards
tioenrichment and amplification of chirality has been recog- the other enantiomer (Fig. 16b). In the context of BH, this work
nized as a valuable method to induce a preferred chirality to highlights that asymmetric photosynthesis by CPL is a potent
a range of assemblies and polymers.182,183,354,415,416 On the mechanism that can be exploited to direct deracemization
contrary, the implementation of CPL as a trigger to direct processes when coupled to an amplification phenomenon.
auto-catalytic processes towards enantiopure small organic
molecules has been scarcely investigated.
CPL was successfully used in the realm of the Soai reaction 5. Theories for the emergence of BH
to direct its outcome, either by using a chiroptical switchable
additive, or by asymmetric photolysis of a racemic substrate. Physical fields, CPL, polarized particles, polarized spins, chiral
In 2004, Soai et al. illuminated for 48 h a photoresolvable chiral surfaces and SMSB processes have been presented as potential
olefin with l- or r-CPL, and mixed it with the reactants of candidates for the emergence of chiral biases in prebiotic
the Soai reaction to afford (S)- or (R)-5-pyrimidyl alkanol, molecules. Their main properties are summarized in Table 1.
respectively, in e.e. higher than 90%.417 In 2005, the photo- The plausibility of the occurrence of these biases under the
lyzate of a pyrimidyl alkanol racemate acted as an asymmetric conditions of the primordial universe has also been evoked for
catalyst for its own formation reaching e.e. greater than certain physical fields (such as CPL or CISS). However, it is
99.5%.418 The enantiomeric excess of the photolyzate was important to provide a more global overview of the current
below the detection level of chiral HPLC instrument but was theories that tentatively explain the following puzzling ques-
amplified thanks to the SMSB process. tions: where, when and how did the molecules of life reach a
In 2009, Vlieg et al. coupled CPL with Viedma ripening to homochiral state? At which point of this undoubtedly intricate
achieve complete and deterministic mirror-symmetry breaking.419 process did life emerge?
Previous investigation revealed that the deracemization by attri-
tion of the Schiff base of phenylglycine amide (rac-1, Fig. 16a) 5.1 Terrestrial or extra-terrestrial origin of BH?
always occurred in the same direction, the (R)-enantiomer, as a The enigma of the emergence of BH might potentially be solved
probable result of minute levels of chiral impurities.372 CPL was by finding the location of the initial chiral bias, might it be
envisaged as a potent chiral physical field to overcome this chiral on earth or elsewhere in the universe. The ‘panspermia’
interference. Irradiation of solid–liquid mixtures of rac-1 indeed hypothesis,424 according to which living organisms were trans-
led to complete deracemization, the direction of which was planted to earth from another solar system, sparked interest on
directly correlated to the circular polarization of light. Control the extra-terrestrial origin of BH, but the fact that such a high
experiments indicated that the direction of the SMSB process is level of chemical and biological evolution was present on

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Table 1 Potential sources of asymmetry and ‘‘by chance’’ mechanisms for the emergence of a chiral bias in prebiotic and biologically-relevant molecules
Review Article

Truly/
falsely Extent of Selected
Type chiral Direction induction Scope Relevance to BH references
PV Truly Unidirectional, deterministic, (+) Minutea Any chiral molecules PVED: theo. calculations (natural) 44, 53 and 54
or () for a given molecule polarized particles: asymmetric
destruction of racematesb
MChD Truly Bidirectional, (+) or () depending on the Minutec Chiral molecules with high Proceed with unpolarised light 137
relative orientation of light and magnetic gNCD and gMCD values
field
Aligned magnetic Falsely Bidirectional, (+) or () depending on the Minuted Large supramolecular Ubiquitous natural physical fields 161
field, gravity and relative orientation of angular momentum aggregates
rotation and effective gravity
Vortices Truly Bidirectional, (+) or () depending on Minuted Large objects or aggregates Ubiquitous natural physical field 151 and 160

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the direction of the vortices (pot, present in hydrothermal vents)
CPL Truly Bidirectional, (+) or () depending on Low to Chiral molecules with Asymmetric destruction of racemates 58
the direction of CPL Moderatee high gNCD values
Spin-polarized Truly Bidirectional, (+) or () depending Low to high f Any chiral molecules Enantioselective adsorption/ 233
electrons (CISS on polarization crystallization of racemate,
effect) asymmetric synthesis
Chiral surfaces Truly Bidirectional, (+) or () depending on Low to excellent Any adsorbed chiral molecules Enantioselective adsorption of 238 and 244
surface chirality racemates
SMSB na Bidirectional, stochastic distribution Low to excellent Conglomerate-forming Resolution of racemates 55 and 382
(crystallization) of (+) or () for repeated processes molecules
SMSB (asymmetric na Bidirectional, stochastic distribution Low to excellent Soai reaction To be demonstrated 312
auto-catalysis) of (+) or () for repeated processes
Chance mechanisms na Bidirectional, stochastic distribution Minuteg Any chiral molecules To be demonstrated 17 and 420–
of (+) or () for repeated processes 422
a
PVED E 1012–1015 kJ mol1.53 b However, experimental results are not conclusive (see Part 3.2(b)). c e.e.MChD = gMChD/2 with gMChD E (gNCD  gMCD)/2. NCD: natural circular dichroism.
MCD: magnetic circular dichroism. For the resolution of Cr complexes,137 e.e. = k  B with k = 105 T1 at l = 695.5 nm. d The minute chiral induction is amplified upon aggregation leading to
homochiral helical assemblies.423 e For photolysis, e.e. depends both on g and the extent of reaction (see eqn (2) and the text in part 3.2(a)). Up to a few e.e. percent have been observed
experimentally.197–199 f Recently, spin-polarized SE through the CISS effect have been implemented as chiral reagents with relatively high e.e. values (up to a ten percent) reached for a set of
reactions.236 g The standard deviation for 1 mole of chiral molecules is of 1.9  1011.126na: not applicable.
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celestial objects has not been supported by any scientific

evidence.44 Accordingly, terrestrial and extra-terrestrial scenar-
ios for the original chiral bias in prebiotic molecules will be
considered in the following.
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(a) Terrestrial origin of BH. A range of chiral influences

have been evoked for the induction of a deterministic bias to
primordial molecules generated on earth. Enantiospecific
adsorptions or asymmetric syntheses on the surface of abun-
dant minerals have long been debated in the context of
BH44,238–242 since no significant bias of one enantiomorphic
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crystal or surface over the other has been measured when

counting is averaged over several locations on earth.257,258 Prior
calculations supporting PVED at the origin of excess of L-quartz
over D-quartz114,425 or favouring the A-form of kaolinite426 are
thus contradicted by these observations. Abyssal hydrothermal
vents during the Hadean/Eo-Archaean eon are argued as the
most plausible regions for the formation of primordial organic
molecules on the early earth.427 Temperature gradients may
have offered the different conditions for the coupled autocata-
lytic reactions and clays may have acted as catalytic sites.347
However, chiral inductors in these geochemically reactive habi-
tats are hypothetical, even though vortices60 or CISS occurring
at the surfaces of greigite has been mentioned recently.428 CPL
Fig. 17 (a) A fragment of a meteorite landed in Murchison, Australia, in
and MChD are not potent asymmetric forces on earth as a 1969, exhibited at the National Museum of Natural History (Washington).
result of low levels of circular polarization detected for the (b) Scheme of the preparation of interstellar ice analogues. A mixture of
former and small anisotropic factors of the latter.429–431 PVED primitive gas molecules is deposited and irradiated under vacuum on a
is an appealing ‘‘intrinsic’’ chiral polarization of matter but its cooled window. Composition and thickness are monitored by infrared
spectroscopy. Reprinted from ref. 434 with permission from MDPI. Copy-
implication in the emergence of BH is questionable (Part 2).126
right 2019. Licensee MDPI under Creative Commons Attribution 4.0
Alternatively, theories suggesting that BH emerged from International License https://creativecommons.org/licenses/by/4.0/.
scratch, i.e. without any involvement of the chiral discriminat-
ing sources mentioned in Part 2–3 and SMSB processes (Part 4),
have been mentioned in the literature for a long time,420 and scenario in Fig. 11). Hazen notably argued that nucleation
variant versions appeared sporadically. Herein, these mechan- processes governing auto-catalytic events occurring at the sur-
isms are named ‘‘random’’ or ‘‘by chance’’ and are based on face of crystals are rare and thus a kinetic bias can emerge from
probabilistic grounds only (Table 1). The prevalent form comes an initially unbiased set of prebiotic racemic molecules.239
from the fact that a racemate is very unlikely made of exactly Random and by chance scenarios towards BH might be attrac-
equal amounts of enantiomers, due to natural fluctuations tive on a conceptual view but lack experimental evidence.
described statistically like coin tossing.126,432 One mole of (b) Extra-terrestrial origin of BH. Scenarios suggesting a
chiral molecules actually exhibits a standard deviation of terrestrial origin behind the original enantiomeric imbalance
1.9  1011. Putting into relation this statistical variation and leave a question unanswered: how an earth-based mechanism
putative strong chiral amplification mechanisms and evolu- can explain enantioenrichment in extra-terrestrial samples?59,433
tionary pressures, Siegel suggested that homochirality is an However, to stray from ‘‘geocentrism’’ is still worthwhile; another
imperative of molecular evolution.17 However, the probability plausible scenario is the exogenous delivery on earth of enantio-
to get both homochirality and life emerging from statistical enriched molecules relevant for the appearance of life. The body
fluctuations at the molecular scale appears very unlikely.35,59,433 of evidence grew from the characterization of organic molecules,
SMSB phenomena may amplify statistical fluctuations up to the especially amino acids and sugars, and their respective optical
homochiral state, yet the direction of process for multiple occur- purity, in meteorites,59 comets, and laboratory-simulated inter-
rences will be left to chance in the absence of a chiral inducer stellar ices.434
(Part 4). Other theories suggested that homochirality emerges The 100 kg Murchison’s meteorite that fell at Australia in
during the formation of biopolymers ‘‘by chance’’, as a con- 1969 is generally considered as the standard reference for extra-
sequence of the limited number of sequences that can be terrestrial organic matter (Fig. 17a).435 In fifty years, the
possibly contained in a reasonable amount of macromolecules analyses of its composition revealed more than ninety a, b, g
(see Part 5.3).17,421,422 Finally, kinetic processes have also been and d-isomers of C2 to C9 amino acids, diamino acids, and
mentioned in which a given chemical event would have dicarboxylic acids as well as numerous polyols including sugars
occurred to a larger extent for one enantiomer over the other (ribose,436 a building block of RNA), sugar acids and alcohols,
under achiral conditions (see one possible physicochemical but also a-hydroxycarboxylic acids437 and deoxy acids.434

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Unequal amounts of enantiomers were also found with a quasi- aliphatic a-amino acids as previously debated.466,467 Likewise,
exclusive predominance for (S)-amino acids57,285,438–440 ranging CPL in the UV range will produce a wide range of amino
from 0 to 26.3  0.8% e.e. values (highest e.e. being measured acids with a bias towards the (S) enantiomer,195 including
for non-proteinogenic a-methyl amino acids),441 and, when a,a-dialkyl amino acids.468
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they are not racemates, only D-sugar acids with an e.e. of up l- and r-CPL produced by a neutron star are equally emitted
to 82% for xylonic acid have been detected.442 These measure- in vast conical domains in the space above and below its
ments are relatively scarce for sugars and in general need to be equator.35 However, appealing hypotheses were formulated
repeated, notably to definitely exclude their potential contami- against the apparent contradiction that amino acids have
nation by terrestrial environment. Future space missions to always been found as predominantly (S) on several celestial
asteroids, comets and Mars, coupled with more advanced bodies,59 and the fact that CPL is expected to be portioned into
analytical techniques,443 will indubitably lead to a better deter-
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left- and right-handed contributions in equal abundance within

mination of the composition of extra-terrestrial organic matter. the outer space. In the 1980s, Bonner and Rubenstein proposed
The fact that major enantiomers of extra-terrestrial amino acids a detailed scenario in which the solar system, revolving around
and sugar derivatives have the same configuration as the the centre of our galaxy, had repeatedly traversed a mole-
building blocks of life constitutes a promising set of results. cular cloud and accumulated enantio-enriched incoming
To complete these analyses of the difficult-to-access outer grains.430,469 The same authors assumed that this enantioen-
space, laboratory experiments have been conducted by repro- richment would come from asymmetric photolysis induced by
ducing the plausible physicochemical conditions present on synchrotron CPL emitted by a neutron star at the stage of planet
astrophysical ices (Fig. 17b).444 Natural ones are formed in formation. Later, Meierhenrich remarked in addition that, in
interstellar clouds,445,446 on the surface of dust grains from molecular clouds, regions of homogeneous CPL polarization
which condensates a gaseous mixture of carbon, nitrogen and can exceed the expected size of a protostellar disk – or of our
oxygen-based molecules (e.g. H2O, CH3OH, CH4, NH3, and solar system,458,470 allowing a unidirectional enantioenrich-
CO2),447 under the influence of very low temperature (5–15 K)448 ment within our solar system, including comets.24 A solid
and pressure. Subsequent photochemical processes in this scenario towards BH thus involves CPL as a source of chiral
mantle of frost are assumed to lead to complex molecules.449 induction for biorelevant candidates, through photochemical
Since collapsing clouds gave birth to our solar system through processes on the surface of dust grains, and delivery of the
the aggregation of dust grains,450 studies of their composition enantio-enriched compounds on primitive earth by direct grain
receive a keen interest to broaden our knowledge about the accretion or by impact471 of larger objects (Fig. 18).472–474
prebiotic environment. Experiments on simulated interstellar The high enantiomeric excesses detected for (S)-isovaline in
ices support the formation of many proteinaceous amino certain stones of the Murchison’s meteorite (up to 15.2  0.2%)
acids,451,452 and building blocks of RNA and DNA such as suggested that CPL alone cannot be at the origin of this
sugars,453 like ribose454 and deoxyribose,455 as well as nucleo- enantioenrichment.285 The broad distribution of e.e. values
bases (adenine, cytosine, uracil and thymine for example).456 (0–15.2%) and the abundance ratios of isovaline relatively to
These molecules were obtained with no significant bias from other amino acids also point to (S)-isovaline (and probably
the ideal racemic composition which supports their abiotic other amino acids) being formed through multiple synthetic
origin.444 However, when similar experiments are conducted processes that occurred during the chemical evolution of the
under CPL irradiation, amino acids are generated with significant meteorite.440 Finally, based on the anisotropic spectra,188 it is
biases towards one enantiomer as described in Part 3.2(a).204,205 highly plausible that other physiochemical processes, e.g. race-
The occurrence of CPL-driven photochirogenesis on inter- mization coupled to phase transitions or coupled non-
stellar dust grains was supported by the detection of near- equilibrium/equilibrium processes,378,475 have led to a change
infrared light with significant circular polarization degrees in the ratio of enantiomers initially generated by UV-CPL.59 In
(up to 22%),457 in parsec-sized star-forming regions, such as addition, a serious limitation of the CPL-based scenario shown
massive molecular clouds.458–464 Cosmic circularly polarized in Fig. 18 is that significant enantiomeric excesses can only be
photons arise from synchrotron radiations emitted by neutron reached at high conversion, i.e. by decomposition of most of
stars, remnants of supernovae explosions,35 through brems- the organic matter (see eqn (2) in Part 3.2(a)). Even though
strahlung, dichroic scattering and/or light extinction (along there is a solid foundation for CPL being involved as an initial
lined up grains).465 In addition, although it was not directly inducer of chiral bias in extra-terrestrial organic molecules,
observed due to dust shielding, models predicted the genera- chiral influences other than CPL cannot be excluded. Induction
tion of vacuum ultraviolet (VUV) and UV-CPL under these and enhancement of optical purities by physicochemical pro-
conditions,459 i.e. spectral regions of light absorbed by amino cesses occurring at the surface of meteorites and potentially
acids and sugars. Photolysis by broad band and optically involving water and the lithic environment have been evoked
impure CPL is expected to yield lower enantioenrichments than but have not been assessed experimentally.285
those obtained experimentally by monochromatic and quasi- Asymmetric photoreactions431 induced by MChD can also be
perfect circularly polarized synchrotron radiation (see Part 3.2a).198 envisaged notably in a neutron star environment, of tremendous
However, a broad band CPL is still capable of inducing chiral magnetic fields (108–1012 T) and synchrotron radiations.35,476
bias by photolysis of an initially abiotic racemic mixture of Spin-polarized electrons (SPEs), another potential source of

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Fig. 18 CPL-based scenario for the emergence of BH following the seeding of the early earth with extra-terrestrial enantio-enriched organic molecules.
Adapted from ref. 474 with permission from Wiley-VCH, copyright 2015.

asymmetry, can potentially be produced upon ionizing irradia- Regarding on whether homochirality happens before or after
tion of ferrous magnetic domains present in interstellar dust the appearance of life discriminates between purely abiotic and
particles, aligned by enormous magnetic fields produced by a biotic theories, respectively (Fig. 19). In between these two
neutron star. One enantiomer from a racemate in a cosmic extreme cases, homochirality could have emerged during the
cloud could adsorb enantiospecifically on the magnetized dust formation of primordial polymers and/or their evolution
particle. In addition, meteorites contain magnetic metallic towards more elaborated macromolecules.
centres that can act as asymmetric reaction sites upon genera- (a) Enantiomeric cross-inhibition. The puzzling question
tion of SPEs. Finally, polarized particles such as antineutrinos regarding primeval functional polymers is whether they form
(the SNAAP model226–228) have been proposed as a determinis- from enantiopure, enantio-enriched, racemic or achiral building
tic source of asymmetry, at work in the outer space. Radio- blocks. A theory that has found great support in the chemical
racemization must potentially be considered as a jeopardizing community is that homochirality was already present at the stage
factor in that specific context.44,477,478 Further experiments are of the primordial soup, i.e. the building blocks of life were
needed to probe whether these chiral influences have played a enantiopure. Proponents of the purely abiotic origin of homo-
role in the generation of the enantiomeric imbalances detected chirality mostly refer to the inefficiency of polymerization
in celestial bodies. reactions when conducted from mixtures of enantiomers. More
precisely, the term enantiomeric cross-inhibition was coined to
5.2 Purely abiotic scenarios describe experiments for which the rate of the polymerization
Emergence of life and biomolecular homochirality must be reaction and/or the length of the polymers were significantly
tightly linked,46,479,480 but in such a way that needs to be reduced when non-enantiopure mixtures were used instead of
cleared up. As recalled recently by Glavin, homochirality by enantiopure ones.24,44 Seminal studies were conducted by
itself cannot be considered as a biosignature.59 Non proteino- oligo- or polymerizing a-amino acid N-carboxy-anhydrides
genic amino acids are predominantly (S) and abiotic physico- (NCAs) in the presence of various initiators. Idelson and Blout
chemical processes can lead to enantio-enriched molecules. observed in 1958 that (R)-glutamate-NCA added to the reaction
However, it has been widely substantiated that polymers of life mixture of (S)-glutamate-NCA led to a significant shortening of
(proteins, DNA, and RNA) as well as lipids need to be enantio- the resulting polypeptides, inferring that (R)-glutamate pro-
pure to be functional. Considering the NASA definition of life, voked the chain termination of (S)-glutamate oligomers.483
‘‘a self-sustaining chemical system capable of Darwinian evolu- Lundberg and Doty also observed that the rate of polymeriza-
tion’’,481 and the ‘‘widespread presence of ribonucleic acid tion of (R)/(S) mixtures of a glutamate-NCA and the mean chain
(RNA) cofactors and catalysts in today’s terran biosphere’’,482 length reached at the end of the polymerization were decreased
a strong hypothesis for the origin of Darwinian evolution and relative to those of pure (R)- or (S)-glutamate-NCA.485,486 Similar
life is ‘‘the abiotic formation of long-chained RNA polymers’’ studies for oligonucleotides were performed with an enantiopure
with the ability to self-replicate.309 Current theories differ template to replicate activated complementary nucleotides. Joyce
by placing the emergence of homochirality at different times et al. showed in 1984 that guanosine oligomerization, directed by
of the chemical and biological evolutions leading to life. a poly-D-cytosine template, was inhibited when conducted with a

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Fig. 19 Possible connections between the emergences of life and homochirality at the different stages of the chemical and biological evolutions.
Possible mechanisms leading to homochirality are indicated below each of the three main scenarios. Some of these mechanisms imply an initial chiral
bias which can be of terrestrial or extra-terrestrial origins as discussed in Part 5.1. LUCA = Last Universal Cellular Ancestor.

racemic mixture of activated mononucleotides.484 The L residues cause enantiomer and racemate to have different physicochem-
are predominantly located at the chain-end of the oligomers, ical properties and this can be exploited to enrich a scalemic
acting as chain terminators, thus decreasing the yield of oligo-D- material into one enantiomer under strictly achiral conditions.
guanosine. A similar conclusion was reached by Goldanskii and This phenomenon of self-disproportionation of the enantio-
Kuz’min upon studying the dependence of the length of enantio- mers (SDE) is not rare for organic molecules and may occur
pure oligonucleotides on the chiral composition of the reactive through a wide range of physicochemical processes.61 SDE with
monomers.429 Interpolation of their experimental results with a molecules of life such as amino acids and sugars is often
mathematical model led to the conclusion that the length of discussed in the framework of the emergence of BH. SDE often
potent replicators will dramatically be reduced in the presence of occurs during crystallization as a consequence of the difference
enantiomeric mixtures reaching a value of 10 monomer units at in solubility between racemic and enantiopure crystals, and its
best for a racemic medium. implementation to amino acids was exemplified by Morowitz as
Finally, the oligomerization of activated racemic guanosine early as 1969.495 It was confirmed later that a number of amino
was also inhibited on DNA and PNA templates.487 The latter acids display high eutectic e.e. values which allows very high
being achiral, it suggests that enantiomeric cross-inhibition is e.e. values to be present in solution, even from moderately
intrinsic to the templated oligomerization process involving biased enantiomeric mixtures.496 Serine is the most striking
complementary nucleobases. example since a virtually enantiopure solution (499% e.e.) is
(b) Propagation and enhancement of the primeval chiral obtained at 25 1C under solid–liquid equilibrium conditions
bias. Studies demonstrating enantiomeric cross-inhibition dur- starting from a 1% e.e. mixture only.497 Enantioenrichment was
ing polymerization reactions have led the proponents of purely also reported for various amino acids after consecutive evapora-
abiotic origin of BH to propose several scenarios for the tions of their aqueous solutions498 or preferential kinetic dis-
formation of building blocks of life in an enantiopure form. solution of their enantiopure crystals.499 Interestingly, the
In this regard, racemization appears as a redoubtable opponent eutectic e.e. values can be increased for certain amino acids
considering that harsh conditions – intense volcanism, asteroid by the addition of simple achiral molecules such as carboxylic
bombardment and scorching heat488,489 – prevailed between acids.500 DL-Cytidine, DL-adenosine and DL-uridine also form
earth formation, 4.5 billion years ago, and the appearance of racemic crystals and their scalemic mixture can thus be
life, 3.5 billion years ago at the latest.490,491 At that time, enriched towards the D enantiomer in the same way provided
deracemization inevitably suffered from its nemesis, racemiza- t that the solution is saturated in both D and DL sugars.501 SDE
tion, which may take place in days or less in a hot alkaline of amino acids does not occur solely during crystallization;502
aqueous medium.35,301,492–494 e.g. sublimation of near-racemic samples of serine yields a
Several scenarios have considered that initial enantiomeric sublimate which is highly enriched in the major enan-
imbalances have probably been decreased by racemization but tiomer.503 Amplification of e.e. by sublimation has also been
not eliminated. Abiotic theories thus rely on processes that reported for other scalemic mixtures of amino acids,504–506 or
would be able to amplify tiny enantiomeric excesses (likely { for a racemate mixed with a non-volatile optically pure amino
1% e.e.) up to the homochiral state. Intermolecular interactions acid.507 Alternatively, amino acids were enantio-enriched by

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simple dissolution/precipitation of their phosphorylated deri- The influence of a-amino acids on the synthesis of RNA
vatives in water.508 precursors was also probed. Along this line, Blackmond and
It is likely that prebiotic chemistry has linked amino acids, co-workers reported that ribo- and arabino-amino oxazolines
sugars and lipids in a way that remains to be determined. were enantio-enriched towards the expected D configuration
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Merging the organocatalytic properties of amino acids with the when 2-aminooxazole and (RS)-glyceraldehyde were reacted in
aforementioned SDE phenomenon offers a pathway towards the presence of (S)-proline (Fig. 20, (3)).514 When coupled with
enantiopure sugars.509 The aldol reaction between 2-chloro- the SDE of the reacting proline (1% e.e.) and of the enantio-
benzaldehyde and acetone was found to exhibit a strongly enriched product (20–80% e.e.), the reaction yielded enantio-
positive non-linear effect, i.e. the e.e. in the aldol product is pure crystals of ribo-amino-oxazoline. (S)-Proline does not act
drastically higher than that expected from the optical purity of as a mere catalyst in this reaction but rather traps the
the engaged amino acid catalyst.497 Again, the effect was
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(S)-enantiomer of glyceraldehyde, thus accomplishing a formal

particularly strong with serine since nearly racemic serine resolution of the racemic starting material. The latter reaction
(1% e.e.) and enantiopure serine provided the aldol product can also be exploited in the opposite way to resolve a racemic
with the same enantioselectivity (ca. 43% e.e., Fig. 20, (1)). mixture of proline in the presence of enantiopure glyceralde-
Enamine catalysis in water was employed to prepare glyceral- hyde (Fig. 20, (4)). This dual substrate/reactant behaviour
dehyde, the probable synthon towards ribose and other sugars, motivated the same group to test the possibility of synthetizing
by reacting glycolaldehyde and formaldehyde in the presence enantio-enriched amino acids with D-sugars. The hydrolysis of
of various enantiopure amino acids. It was found that all 2-benzyl a-amino nitrile yielded the corresponding a-amino
(S)-amino acids, except (S)-proline, provided glyceraldehyde with amide (precursor of phenylalanine) with various e.e. values
a predominant R configuration (up to 20% e.e. with (S)-glutamic and configurations depending on the nature of the sugars.515
acid, Fig. 20, (2)).65,510 This result coupled to SDE furnished a Notably, D-ribose provided the product with 70% e.e. biased in
small fraction of glyceraldehyde with 84% e.e. Enantio-enriched favour of unnatural (R)-configuration (Fig. 20, (5)). This result,
tetrose and pentose sugars are also produced by means of aldol which is apparently contradictory with such process being
reactions catalysed by amino acids and peptides in aqueous buffer involved in the primordial synthesis of amino acids, was solved
solutions, albeit in modest yields.511–513 by finding that the mixture of four D-pentoses actually favoured
the natural (S) amino acid precursor. This result suggests an
unanticipated role of prebiotically relevant pentoses such as
D-lyxose in mediating the emergence of amino acid mixtures
with a biased (S) configuration.
How the building blocks of proteins, nucleic acids and lipids
would have interacted between each other before the emer-
gence of life is a subject of intense debate. The aforementioned
examples in which prebiotic amino acids, sugars, and nucleo-
tides would have mutually triggered their formation are actually
not the privileged scenario of ‘origin of life’ practitioners. Most
theories infer relationship at a more advanced stage of the
chemical evolution. In the ‘‘RNA world’’,516 a primordial RNA
replicator catalysed the formation of the first peptides and
proteins. Alternative hypotheses are that proteins (‘‘metabolism
first’’ theory) or lipids517 originated first518 or that RNA, DNA
and proteins emerged simultaneously by continuous and
reciprocal interactions, i.e. mutualism.519,520 It is commonly
considered that homochirality would have arisen through
stereoselective interactions between the different types of bio-
molecules, i.e. chirally matched combinations would have
conducted to potent living systems whilst the chirally mis-
matched combinations would have declined. Such theory has
notably been proposed recently to explain the splitting of lipids
into opposite configurations in archaea and bacteria (known as
the ‘lipide divide’)521 and their persistence.522 However, these
theories do not address the fundamental question of the initial
chiral bias and its enhancement.
SDE appears as a potent way to increase the optical purity of
some building blocks of life but its limited scope, efficiency (an
Fig. 20 Selected catalytic reactions involving amino acids and sugars, and initial bias Z1% e.e. is required) and productivity (high optical
leading to the enantioenrichment of prebiotically relevant molecules. purity is reached at the cost of the mass of the material) appear

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detrimental for explaining the emergence of chemical homo- towards homochiral sequences.530 Excess factors, calculated
chirality. An additional drawback of SDE is that the enantio- relatively to a stereorandom polymerization process, were higher
enrichment is only local, i.e. the overall material remains for the longer oligomers.531 In the case of Leu, the presence of
unenriched. SMSB processes as those mentioned in Part 4 are (a)-quartz as a 1 : 1 mixture of the D and L enantiomorphs was
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consequently considered as more probable alternatives towards found to improve the stereoselectivity of the polymerization
homochiral prebiotic molecules. They disclose two major process thanks to the selective adsorption of the more regular
advantages: (i) a tiny fluctuation around the racemic state homochiral peptides on the quartz surface.532 The combination
might be amplified up to the homochiral state in a determi- of (a)-quartz and a reaction mixture biased in favour of one of
nistic manner, (ii) the amount of prebiotic molecules generated the amino-acid enantiomer (20% e.e.) was necessary to get
throughout these processes is potentially very high (e.g. in homochiral sequences as the major component of the peptide
Viedma-type ripening experiments).383 Even though experi- stereoisomers.533 The length of peptides reached under these
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mental reports of SMSB processes have appeared in the litera- conditions remains limited (n o 10) which lets the question of
ture for the last 25 years, none of them display conditions that how long and well-structured homochiral peptides sequences
appear relevant to prebiotic chemistry. The quest for small- emerged from the prebiotic soup unanswered. One possibility
molecule reactions, exhibiting asymmetric replication and per- is that their formation was triggered by a ribozyme, i.e. that the
sisting high selectivity, compatible with primeval conditions construction of functional and catalytic RNAs preceded the
has recently been suggested as a key challenge for organic generation of peptides and proteins.516
chemists.523 Studying complex networks of organic chemical Synthetic chemistry aimed at mimicking prebiotic condi-
reactions524 instead of single auto-catalytic events might shed tions for the synthesis of RNA oligomers has provided some
light on cooperative systems from which homochirality might support along this direction. Oligomers of up to 55 nucleotides
emerge.302 In this context, open systems with a continuous can be synthetized by successive elongation of a decanucleotide
supply of reactants are better suited to reach homochiral NESS with enantiopure nucleotides on Na+-montmorillonite.288
and it is expected that current progresses made in studying the Subsequent experiments have then been conducted directly
self-assembly process under dissipative conditions525 will be from racemic mixtures of activated mononucleotides in order
extended to chiral reaction networks.41 to probe the possibility of generating homochiral RNA oligo-
mers, again with Na+-montmorillonite. Activated racemic
5.3 Homochirality through polymerization adenosine oligomerized with comparable efficiency to enantio-
Purely abiotic theory is based on the argument that enantio- pure D-monomers discarding significant enantiomeric cross-
meric cross-inhibition will ineluctably impede the formation of inhibition.534 The distribution of oligomer stereoisomers (up to
potent replicators. However, the fact that chemical processes 8 units under these conditions) appeared to be biased in favour
may follow dramatically different mechanisms depending on of homochiral sequences. Deeper investigation of these
the conditions has been overlooked. Likewise, stereoselective reactions confirmed important and modest chiral selection in
and non-selective polymerization reactions which allow regular the oligomerization of activated adenosine535–537 and uridine,
and random arrangements of the monomer enantiomers along respectively.537 The co-oligomerization reaction of activated
the polymer backbone, respectively, are ubiquitous in polymer adenosine and uridine exhibited greater efficiency (up to 74%
science, and cross-inhibition is likely to be the exception rather homochiral selectivity for the trimers) compared with the
than the norm.526,527 separate reactions of enantiomeric activated monomers.538
(a) Stereoselective polymerization or ligation. Along this Again, the length of oligomers detected in these experiments
line, experimental efforts have been devoted to demonstrate the is far below the estimated number of nucleotides necessary to
preferential formation of isotactic over heterochiral macro- instigate chemical evolution.540 This questions the plausibility
molecules for reactions initiated with racemic mixture of amino of RNA as the primeval informational polymer. Joyce and
acids. An additional objective of these studies was to demon- co-workers evoked the possibility of a more flexible chiral
strate the emergence of homochiral oligomers, of a sufficient polymer based on acyclic nucleoside analogues as an ancestor
size to sustain a secondary structure. It is indeed well estab- of the more rigid furanose-based replicators but this hypothesis
lished that the helical configuration present in peptides tends has not been probed experimentally.541
to improve further the stereoselectivity of the polymerization Replication provided an advantage for achieving stereo-
process, through preferential helical growth.485,528 Goldberg selectivity provided that reactivity of chirally mismatched
studied the ligation of enantiopure amino esters, dipeptides combinations are disfavoured relative to homochiral ones.
and tripeptides (derived from alanine, aspartic acid and gly- A 32-residue peptide replicator was designed to probe the
cine) to racemic mixtures of activated alanine or aspartic acid relationship between homochirality and self-replication.539
amino esters in DMF and found a modest but significant bias Electrophilic and nucleophilic 16-residue peptide fragments
towards the formation of homochiral peptides in the majority of the same handedness were preferentially ligated, even in
of cases.529 More recent investigations by the group of Luisi on the presence of their enantiomers (ca. 70% of diastereomeric
the polymerization of racemic a-amino acid NCAs of leucine excess was reached when peptide fragments EL, ED, NE, and ND
(Leu), isoleucine (Ile), tryptophan (Trp) and glutamic acid were engaged, Fig. 21). The replicator entails a stereoselective
(Glu) in buffered aqueous solution also indicated a slight bias autocatalytic cycle, for which all bimolecular steps are faster for

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in the presence of heterochiral tetramers. These results raised

the possibility that a similar experiment performed with the
whole set of stereoisomers would have generated ‘‘predomi-
nantly homochiral’’ (L) and (D) sequence libraries of relatively
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long p-RNA oligomers. The studies with replicating peptides or

auto-oligomerizing pyranosyl tetramers undoubtedly yield pep-
tides and RNA oligomers that are both longer and optically
purer than in the aforementioned reactions (Part 5.2) involving
activated monomers. Further work is needed to delineate
whether these elaborated molecular frameworks could have
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emerged from the prebiotic soup.

Replication in the aforementioned systems stems from the
stereoselective non-covalent interactions established between
products and substrates. Stereoselectivity in the aggregation of
non-enantiopure chemical species is a key mechanism for the
emergence of homochirality in the various states of matter.543
The formation of homochiral versus heterochiral aggregates
with different macroscopic properties led to enantioenrichment
of scalemic mixtures through SDE as discussed in Part 5.2.
Alternatively, homochiral aggregates might serve as templates
at the nanoscale. In this context, the ability of serine (Ser) to
preferentially form octamers when ionized from its enantio-
pure form is intriguing.544 Moreover, (S)-Ser in these octamers
can be substituted enantiospecifically by prebiotic molecules
(notably D-sugars)545 suggesting an important role of this
amino acid in prebiotic chemistry. However, the preference
for homochiral clusters is strong but not absolute and other
clusters form when the ionization is conducted from racemic
Ser,546,547 making the implication of serine clusters in the
emergence of homochiral polymers or aggregates doubtful.
Lahav and co-workers investigated in detail the correlation
Fig. 21 Top: Schematic representation of the stereoselective replication
of peptide residues with the same handedness. Below: Diastereomeric between aggregation and reactivity of amphiphilic activated
excess (de) as a function of time. de (%)= [(TLL + TDD)  (TLD + TDL)]/ racemic a-amino acids.548 These authors found that the stereo-
Ttotal.539 selectivity of the oligomerization reaction is strongly enhanced
under conditions for which b-sheet aggregates are initially
present549 or emerge during the reaction process.550–552 These
matched versus unmatched pairs of substrate enantiomers, supramolecular aggregates serve as templates in the propaga-
thanks to self-recognition driven by hydrophobic inter- tion step of chain elongation leading to long peptides and co-
actions.542 The process is very sensitive to the optical purity peptides with a significant bias towards homochirality. Large
of the substrates, fragments embedding a single (S)/(R) amino enhancement of the homochiral content was detected, notably
acid substitution lacked significant auto-catalytic properties. for the oligomerization of rac-Val NCA in the presence of 5% of
On the contrary, stereochemical mismatches were tolerated in an initiator (Fig. 22).551 Racemic mixtures of isotactic peptides
the replicator; single mutated templates were able to couple are desymmetrized by adding chiral initiators551 or by biasing
homochiral fragments, a process referred to as ‘‘dynamic the initial enantiomer composition.553,554 The interplay
stereochemical editing’’. between aggregation and reactivity might have played a key
Templating also appeared to be crucial for promoting the role for the emergence of primeval replicators.
oligomerization of nucleotides in a stereoselective way. The (b) Heterochiral polymers. DNA and RNA duplexes as well
complementarity between nucleobase pairs was exploited to as protein secondary and tertiary structures are usually desta-
achieve homochiral sequences of pyranosyl-RNA.421 Activated bilized by incorporating chiral mismatches, i.e. by substituting
homochiral tetramers containing hemi self-complementary the biological enantiomer by its antipode. As a consequence,
base sequences (pr(GCCG)-2 0 3 0 cyclophosphate, pr = pyranosyl- heterochiral polymers, which can hardly be avoided from
ribo) yielded relatively long oligomers (a ten of units) under reactions initiated by racemic or quasi racemic mixtures of
mild conditions. Heterochiral tetramers (e.g. DDDL, DDLD, and enantiomers, are mainly considered in the literature as hurdles
DLDD stereoisomers) were found to be poorly reactive under for the emergence of biological systems. Several authors have
the same conditions. Importantly, the oligomerization of the nevertheless considered that these polymers could have formed
homochiral tetramer was only slightly affected when conducted at some point of the chemical evolution process towards potent

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blocks are still complex relative to what is expected to be readily

generated from the prebiotic soup. Brewer and Davis hypothe-
sized a set of more realistic polymers that could have emerged
from very simple building blocks such as formaldehyde,
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a-substituted ketones, aldehydes, alkenes, amino-acids or

a-hydroxy acids.422 Polymers with random arrangement of (R)
and (S) stereogenic centres are expected to be replicated
through recognition of their chiral sequence. Such chiral
encoding559 might allow the emergence of replicators with
specific catalytic properties. If one considers that the large
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number of possible sequences exceeds the number of mole-

cules present in a reasonably sized sample of these chiral
informational polymers, then their mixture will not constitute
a perfect racemate since certain heterochiral polymers will lack
their enantiomers. This argument of the emergence of homo-
chirality or of a chiral bias ‘‘by chance’’ mechanism through the
polymerization of a racemic mixture was also put forward
previously by Eschenmoser421 and Siegel.17 This concept has
been sporadically probed notably through the template-
controlled copolymerization of the racemic mixtures of two
different activated amino acids.560–562 However, in the absence
of any chiral bias, it is more likely that this mixture will yield
informational polymers with pseudo enantiomeric like struc-
tures rather than the idealized chirally uniform polymers (see
Part 5.4). Finally, the same authors also considered that pairing
Fig. 22 Stereoselective polymerization of rac-Val N-carboxyanhydride in and replication between heterochiral polymers could operate
the presence of 5 mol% (square) or 25 mol% (diamond) of n-butylamine
through interaction between their helical structures, rather
as the initiator. Homochiral enhancement is calculated relative to the
binomial distribution of the stereoisomers. Reprinted from ref. 551 with than on their individual stereogenic centres (Fig. 23).422
permission from Wiley-VCH, copyright 2008. On this specific point, it should be emphasized that the helical
conformation adopted by the main chain of certain types of
polymers can be ‘‘amplified’’, i.e. that single handed fragments
biological polymers. This is notably based on the observation may form even if composed of non-enantiopure building
that the extent of destabilization of heterochiral versus homo- blocks.563 For example, synthetic polymers embedding a modestly
chiral macromolecules depends on a variety of factors, including biased racemic mixture of enantiomers adopt a single-handed
the nature, number, location, and environment of the substitu- helical conformation thanks to the so-called ‘‘majority-rules’’
tions;555 e.g. certain D to L mutations are tolerated in DNA effect.564–566 This phenomenon might have helped to enhance
duplexes.556 Moreover, simulations recently suggested that the helicity of the primeval heterochiral polymers relatively to the
‘‘demi-chiral’’ proteins, which contain a 1 : 1 ratio of (R) and optical purity of their feeding monomers.
(S) a-amino acids, even though less stable than their homo-
chiral analogues, exhibit structural requirements (folding, sub-
strate binding and active sites) suitable for promoting early
metabolism (e.g. t-RNA and DNA ligase activities).557 Likewise,
several racemic membranes, i.e. composed of lipid antipodes,
were found to be of comparable stability to homochiral ones.521
Several scenarios towards BH involve non-homochiral poly-
mers as possible intermediates towards potent replicators.
Joyce proposed a three-phase process towards the formation
of genetic materials assuming the formation of flexible poly-
mers, constructed from achiral or prochiral acyclic nucleoside
analogues, as intermediates towards RNA and finally DNA.541
It was presumed that ribose-free monomers would be more
easily accessed from the prebiotic soup than ribose ones and
that the conformational flexibility of these polymers would
Fig. 23 Principle of chiral encoding in the case of a template consisting of
work against enantiomeric cross-inhibition. Other simplified regions of alternating helicity. The initially formed heterochiral polymer
structures, relative to RNA, have been proposed by others.558 replicates by recognition and ligation of its constituting helical
However, the molecular structures of the proposed building fragments.422

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(c) Theoretical models of polymerization. Several theoreti-

cal models accounting for the homochiral polymerization of
a molecule in the racemic state, i.e. mimicking a prebiotic
stereoselective polymerization process, were developed by
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means of kinetic or probabilistic approaches. As early as

1966, Yamagata proposed that stereoselective polymerization
coupled with different activation energies between reactive
stereoisomers will ‘‘accumulate’’ the slight difference in ener-
gies between their composing enantiomers (assumed to origi-
nate from PVED) to eventually favour the formation of a single
homochiral polymer.108 Amongst other criticisms,124 the unrea-
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listic conditions of perfect stereoselectivity have been pointed

out.567 Yamagata later developed a probabilistic model which
(i) favours ligations between monomers of the same chirality
without discarding chirally mismatched combinations, (ii) gives
an advantage of bonding between L monomers (again thanks to
PVED) and (iii) allows racemization of the monomers and rever-
sible polymerization. Homochirality in that case appears to Fig. 24 The Hochberg model for chiral polymerization in closed systems.
develop much more slowly than the growth of polymers.568 This N = maximum chain length of the polymer, f = fidelity of the feedback
conceptual approach neglects enantiomeric cross-inhibition and mechanism, Q and P are the total concentrations of left-handed and right-
relies on the difference in reactivity between enantiomers which handed polymers, respectively. e(e), k(k), kaa(kaa), kbb(kbb), kba(kba),
kab(kab) denote the forward (reverse) reaction rate constants.64
has not been observed experimentally. The kinetic model devel-
oped by Sandars569 in 2003 received deeper attention as it revealed
some intriguing features of homochiral polymerization processes.
The model is based on the following specific elements: (i) chiral surface- or template-mediated. The emergence of RNA polymers
monomers are produced from an achiral substrate, (ii) cross- with RNA replicase or nucleotide synthase properties during the
inhibition is assumed to stop polymerization, (iii) polymers of a course of the simulation led to amplification of the initial chiral
certain length N catalyse the formation of enantiomers in an bias. Finally, several models show that cross-inhibition is not
enantiospecific fashion (similar to a nucleotide synthetase ribo- a necessary condition for the emergence of homochirality in
zyme), and (iv) the system is open, i.e. the achiral substrate is polymerization processes. Higgs and co-workers considered all
continously produced and polymers develop to a maximum polymerization steps to be random (i.e. occurring with the same
length of N units and then leave the system. By introducing a rate constant) regardless of the nature of condensed monomers
slight difference in the initial concentration values of the (R) and and that a fraction of homochiral polymers catalyzes the for-
(S) enantiomers, bifurcation304 readily occurs, i.e. polymers mation of the monomer enantiomers in an enantiospecific
embedding a single enantiomer are formed. The required condi- manner.577 The simulation yielded homochiral polymers (of both
tions are sufficiently high values of the kinetic constants asso- antipodes) even from a pure racemate under conditions which
ciated with enantioselective production of the enantiomers and favour the catalyzed over non-catalyzed synthesis of the mono-
cross-inhibition. mers. These polymers are referred to as ‘‘chiral living polymers’’
The Sandars model was modified in different ways by several as the result of their auto-catalytic properties. Hochberg modified
groups570–574 to integrate more realistic parameters such as the its previous kinetic reaction scheme drastically by suppressing
possibility for polymers of all lengths to act catalytically in the cross-inhibition (polymerization operates through a stereo-
breakdown of the achiral substrate into chiral monomers selective and cooperative mechanism only), and by allowing
(instead of solely polymers of length N as in the model of fragmentation and fusion of the homochiral polymer chains.578
Sandars).64,575 Hochberg considered in addition a closed The process of fragmentation is irreversible for the longest
chemical system (i.e. the total mass of matter is kept constant) chains, mimicking a mechanical breakage. This breakage
which allows polymers to grow towards a finite length (see represents an external energy input to the system. This binary
reaction scheme in Fig. 24).64 Starting from an infinitesimal e.e. chain fusion mechanism is necessary to achieve SMSB in this
bias (e.e.0 = 5  108%), the model shows the emergence of simulation from infinitesimal chiral bias (e.e.0 = 5  1011%).
homochiral polymers in an absolute but temporary manner. Finally, even though not specifically designed for a polymeriza-
The reversibility of this SMSB process was expected for a closed tion process, a recent model by Ribó and Hochberg shows how
system. Ma and co-workers recently published a probabilistic homochiral replicators could emerge from two or more cataly-
approach which is presumed to better reproduce the emer- tically coupled asymmetric replicators, again without the need
gence of the primeval RNA replicators and ribozymes in the for the inclusion of a heterochiral inhibition reaction.350 Six
RNA World.576 The D-nucleotide and L-nucleotide precursors are homochiral replicators emerge from their simulation by means
set to racemize to account for the behaviour of glyceraldehyde of an open flow reactor incorporating six achiral precursors and
under prebiotic conditions; and the polynucleotide synthesis is replicators in low initial concentrations and minute chiral

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biases (e.e.0 = 5  1018%). These models should stimulate the nowadays living organisms can be a relic of a time in which
quest of polymerization pathways which include stereoselective mirror-image living systems were ‘‘struggling’’. Likewise, to
ligation, enantioselective synthesis of the monomers, replica- rationalize the aforementioned ‘‘lipid divide’’, it has been
tion and cross-replication, i.e. hallmarks of an ideal stereo- proposed that the LUCA of bacteria and archaea could have
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selective polymerization process. embedded a heterochiral lipid membrane, i.e. a membrane

containing two sorts of lipid with opposite configurations.521
5.4 Purely biotic scenarios Several studies also probed the possibility to prepare a
In the previous two sections, the emergence of BH was dated at biological system containing the enantiomers of the molecules
the level of prebiotic building blocks of life (for purely abiotic
theories) or at the stage of the primeval replicators, i.e. at the
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early or advanced stages of the chemical evolution, respectively.

In most theories, an initial chiral bias was amplified yielding
either prebiotic molecules or replicators as single enantiomers.
Others hypothesized that homochiral replicators and then life
emerged from unbiased racemic mixtures by chance, basing
their rationale on probabilistic grounds.17,421,559,577 In 1957,
Fox,579 Rush580 and Wald581 held a different view and indepen-
dently emitted the hypothesis that BH is an inevitable conse-
quence of the evolution of the living matter.44 Wald notably
reasoned that, since polymers made of homochiral monomers
likely propagate faster, are longer and have stronger secondary
structures (e.g. helices), they must have provided sufficient
criteria to the chiral selection of amino acids thanks to the
formation of their polymers under ad hoc conditions. This
statement was supported by experiments showing that stereo-
selective polymerization is enhanced when oligomers adopt a
a-helix conformation.485,528 However, Wald went a step further
by supposing that homochiral polymers of both handedness
would have been generated under the supposedly symmetric
external forces present on prebiotic earth and that primordial
life originated under the form of two populations of organisms,
enantiomers of each other. From then, the natural forces of
evolution led certain organisms to be superior to their enantio-
morphic neighbours leading to life in a single form, as we know
it today. The purely biotic theory of emergence of BH thanks to
biological evolution, instead of chemical evolution for abiotic
theories, was accompanied by large scepticism in the literature
even though the arguments of Wald were developed later on by
others44 and notably by Ageno (sexual reproduction naturally
resolves enantiomeric populations),582 and Kuhn (the stronger
enantiomeric form of life survived in the ‘‘struggle’’).583 More
recently, Green and Jain summarized the Wald theory into the
catchy formula ‘‘Two Runners, One Tripped’’,584 and called for
deeper investigation on routes towards racemic mixtures of
biologically relevant polymers.
The Wald theory by its essence has been difficult to assess
experimentally. On the one side, (R)-amino acids when found in
Fig. 25 Cross-chiral ribozyme. (a) Sequence and secondary structure of
mammals are often related to destructive and toxic effects
the 42.9t ribozyme. Structural evolutions from the starting 16.12t ribozyme
suggesting a lack of complementary with the current biological are indicated as follow: core of the 16.12t ribozyme (black), optimized
machinery in which (S)-amino acids are ultra-predominating. nucleotide sequence (green) and primer binding sites (orange). Red circles
On the other side, (R)-amino acids have been detected in the indicate mutations relative to the core of the starting 16.12t ribozyme.
cell wall peptidoglycan layer of bacteria585 and in various (b) RNA-templated polymerization, demonstrating incorporation of all four
L-NTPs, but not D-NTPs. The experiments are conducted with a L-RNA
peptides of bacteria, archaea, and eukaryotes.16 (R)-Amino
primer connected to the D-ribozyme, in presence of a separate L-RNA
acids in these various living systems have an unknown origin. template, in order to direct the synthesis of a product having the sequence
Certain proponents of the purely biotic theories suggest that 5 0 -GUACG-3 0 . Reproduced with permission from ref. 590. Copyright
the small but general occurrence of (R)-amino acids in 2020. American Chemical Society.

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of life as we know it today. L-Polynucleotides and (R)-poly- scenarios and assert that the solution is likely not expected in a
peptides were synthesized; and expectedly they exhibited chiral near future (due to the difficulty to do all required control
substrate specificity and biochemical properties that mirrored experiments, and fully understand the theoretical background
those of their natural counterparts.586–588 In a recent example, of the putative selection mechanism).53 In parallel, the exis-
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Liu, Zhu and co-workers showed that a synthesized 174-residue tence, and the extent, of a putative link between the different
(R)-polypeptide catalyzes the template-directed polymerization configurations of biologically relevant amino acids and sugars
of L-DNA and its transcription into L-RNA.587 It was also also remains unsolved,591 and only Goldanskii and Kuz’min
demonstrated that the synthesized and natural DNA poly- studied the effects of a hypothetical global loss of optical purity
merase systems operate without any cross-inhibition when in the future.429
mixed together in the presence of a racemic mixture of the Nevertheless, great progress has been made recently for a
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constituents required for the reaction (D- and L primers, D- and better perception of this long-standing enigma. The scenario
L-templates and D- and L-dNTPs). From these impressive results, involving circularly polarized light as a chiral bias inducer is
it is easy to imagine how mirror-image ribozymes would have more and more convincing thanks to operational and analytical
worked independently in the early evolution times of primeval improvements. Increasingly accurate computational studies
living systems. supply precious information, notably about SMSB processes,
One puzzling question concerns the feasibility for a bio- chiral surfaces, and other truly chiral influences. Asymmetric
polymer to synthesize its mirror-image. This has been addressed autocatalytic systems and deracemization processes have also
elegantly by the group of Joyce who demonstrated very recently undoubtedly grown in interest (notably thanks to the dis-
the possibility for a RNA polymerase ribozyme to catalyze coveries of the Soai reaction and the Viedma ripening). Space
the templated synthesis of RNA oligomers of the opposite missions are also an opportunity: to study the in situ organic
configuration.589 The D-RNA ribozyme was selected, through matter, its conditions of transformations, and possible asso-
16 rounds of selective amplification away from a random ciated enantio-enrichment; to elucidate the solar system origin
sequence, for its ability to catalyze the ligation of two L-RNA and its history; and maybe, to find traces of chemicals with
substrates on a L-RNA template. The 16.12t D-RNA ribozyme ‘‘unnatural’’ configurations in celestial bodies, which could
was eventually discovered which exhibited sufficient activity to indicate that the chiral selection of terrestrial BH could be a
generate full-length copies of its enantiomer through the mere coincidence.
template-assisted ligation of 11 oligonucleotides. Variants of The current state of the art indicates that further experi-
this cross-chiral enzyme demonstrated stronger ability to poly- mental investigations of the possible effect of other sources of
merize nucleotide triphosphates (NTP) and trinucleotides.590 asymmetry are needed. Photochirogenesis is attractive in many
Importantly, these designed ribozymes (such as the NTP poly- respects: CPL has been detected in space, e.e. values have been
merase shown in Fig. 25) remain operative in the presence of measured for several prebiotic molecules found on meteorites
racemic substrates and templates. In the hypothesis of a RNA or generated in laboratory-reproduced interstellar ices. However,
world, it is intriguing to consider the possibility of a primordial this detailed postulated scenario still faces pitfalls related to
ribozyme with cross-catalytic polymerization activities. In such the variable sources of extra-terrestrial CPL, the requirement of
a case, one can consider the possibility that enantiomeric finely-tuned illumination conditions (almost full extent of
ribozymes would have existed concomitantly and that evolu- reaction at the right place and moment of the evolutionary
tionary innovation would have favoured the systems based on stages), and the unknown mechanism leading to the amplifica-
D-RNA and (S)-polypeptides leading to the exclusive form of BH tion of the original chiral biases. Strong calls to organic
as present on earth nowadays. Finally, a strongly convincing chemists are thus necessary to discover new asymmetric auto-
evidence for the standpoint of the purely biotic theories would catalytic reactions, maybe through the investigation of complex
be the discovery in sediments of primitive forms of life based and large chemical systems,592 that can meet the criteria of
on a molecular machinery entirely composed of (R)-amino acids primordial conditions.40,41,302,312
and L-nucleic acids. Anyway, the quest for the biological homochirality origin is
fruitful in many aspects. The first concerns one consequence of
the asymmetry of life: the contemporary challenge of synthe-
6. Conclusions and perspectives of sizing enantiopure bioactive molecules. Indeed, many synthetic
biological homochirality studies efforts are directed towards the generation of optically-pure
molecules, to avoid potential side effects of racemic mixtures
Questions accumulated while considering all the possible due to the enantioselectivity of biological receptors. These
origins of the initial enantiomeric imbalance that have ulti- endeavors can undoubtedly draw inspiration from a range of
mately led to biological homochirality. When some hypothesize deracemization and chirality induction processes conducted in
a reason behind its emergence (such as for informational connection with biological homochirality. One example is the
entropic reasons, resulting in evolutionary advantages towards Viedma ripening, which allows the preparation of enantiopure
more specific and complex functionalities),25,350 others wonder molecules displaying potent therapeutic activities.55,593 Other
whether it is reasonable to reconstruct a chronology 3.5 billion efforts are devoted to the building-up of sophisticated experi-
years later.37 Many are circumspect in front of the pile-up of ments and pushing their measurement limits to be able to

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detect tiny enantiomeric excesses, thus strongly contributing Conflicts of interest

to important improvements in scientific instrumentation and
acquiring fundamental knowledge at the interface between There are no conflicts to declare.
chemistry, physics, and biology. Overall, this joint endeavor
This article is licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported Licence.

at the frontier of many fields is also beneficial to materials Acknowledgements

science notably for the elaboration of biomimetic materials and
emerging chiral materials.594,595 The French Agence Nationale de la Recherche is acknowledged
for funding the project AbsoluCat (ANR-17-CE07-0002) to MR.
The GDR 3712 Chirafun from Centre National de la recherche
Scientifique (CNRS) is acknowledged for allowing a collabora-
Abbreviations tive network between partners involved in this review. J. C.
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BH Biological homochirality warmly thanks Dr Benoı̂t Darquié from the Laboratoire de

CISS Chiral-induced spin selectivity Physique des Lasers (Université Sorbonne Paris Nord) for
CD Circular dichroism fruitful discussions and precious advice.
de Diastereomeric excess
DFT Density functional theories Notes and references
DNA Deoxyribonucleic acid
dNTPs Deoxynucleotide triphosphates 1 W. Thomson, Baltimore Lectures on Molecular Dynamics
e.e(s). Enantiomeric excess(es) and the Wave Theory of Light, Cambridge Univ. Press,
EPR Electron paramagnetic resonance Warehouse, 1894, Edition of 1904, p. 619.
Epi Epichlorohydrin 2 K. Mislow, in Topics in Stereochemistry, ed. S. E. Denmark,
FCC Face-centred cubic John Wiley & Sons, Inc., Hoboken, NJ, USA, 2007, pp. 1–82.
GC Gas chromatography 3 B. Kahr, Chirality, 2018, 30, 351–368.
LES Limited enantioselective 4 S. H. Mauskopf, Trans. Am. Philos. Soc, 1976, 66, 1–82.
LUCA Last universal cellular ancestor 5 J. Gal, Helv. Chim. Acta, 2013, 96, 1617–1657.
MCD Magnetic circular dichroism 6 L. Pasteur, C. R. Hebd. Seances Acad. Sci., 1848, 26, 535–538.
MChD Magneto-chiral dichroism 7 C. Djerassi, R. Records, E. Bunnenberg, K. Mislow and
MS Mass spectrometry A. Moscowitz, J. Am. Chem. Soc., 1962, 870–872.
MW Microwave 8 S. J. Gerbode, J. R. Puzey, A. G. McCormick and
NESS Non-equilibrium stationary states L. Mahadevan, Science, 2012, 337, 1087–1091.
NCA N-Carboxy-anhydride 9 G. H. Wagnière, On Chirality and the Universal Asymmetry.
NTPs Nucleotide triphosphates Reflections on Image and Mirror Image, VHCA, Verlag Hel-
NMR Nuclear magnetic resonance vetica Chimica Acta, Zürich (Switzerland), 2007.
OEEF Oriented-external electric fields 10 H.-U. Blaser, Rendiconti Lincei, 2007, 18, 281–304.
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