Phil. Trans. R. Soc.

B (2011) 366, 2878–2884

doi:10.1098/rstb.2011.0130

Research

The origin of biological homochirality

Donna G. Blackmond*
Department of Chemistry, The Scripps Research Institute, La Jolla, CA 92037, USA
The single handedness of biological molecules has fascinated scientists and laymen alike since Pas-
teur’s first painstaking separation of the enantiomorphic crystals of a tartrate salt over 150 years ago.
More recently, a number of theoretical and experimental investigations have helped to delineate
models for how one enantiomer might have come to dominate over the other from what presumably
was a racemic prebiotic world. Mechanisms for enantioenrichment that include either chemical or
physical processes, or a combination of both, are discussed in the context of experimental studies in
autocatalysis and in the phase behaviour of chiral molecules.
Keywords: chirality; amino acids; RNA

1. INTRODUCTION world. On the other hand, discussions of how an

The property of chirality—non-superimposable forms imbalance could have originated here on the Earth
that are mirror images of one another, as are left and often debate the question of whether life was pre-
right hands—is manifest in both molecular and macro- ordained to be based on D-sugars and L-amino acids
scopic objects. As early as 1874, and a quarter century or whether this happened by chance, implying that a
after Pasteur showed that salts of tartaric acid exist as life form based on the opposite chirality might have
mirror-image crystals, van’t Hoff and Le Bel indepen- been just as likely at the outset. Here, physics enters
dently postulated the existence of chiral molecules [1]. the picture: the discovery of parity violation and the
Chiral molecules in living organisms in Nature exist elaboration of one of its consequences, that enantio-
almost exclusively as single enantiomers, a property mers have a very small energy difference between
that is critical for molecular recognition and replication them, led many to consider the implications for bio-
processes and would thus seem to be a prerequisite for logical homochirality [3]. Quantitative estimates of
the origin of life. Yet left- and right-handed molecules this energy difference have been made and revised in
of a compound will form in equal amounts (a racemic the intervening years, but it is clear that it is negligibly
mixture) when we synthesize them in the laboratory in small; while experimental and theoretical work is
the absence of some type of directing template. ongoing, and the question is not yet settled, a relation-
The fact of the single chirality of biological ship between biological homochirality and parity
molecules—exclusively left-handed amino acids and violation is not yet supported by experimental findings.
right-handed sugars—presents us with two questions: Proponents on the ‘chance’ side of this question
First, what served as the original template for biasing point out that absolute asymmetric synthesis—defined
production of one enantiomer over the other in the as the production of enantiomerically enriched pro-
chemically austere, and presumably racemic, environ- ducts in the absence of a chemical or physical chiral
ment of the prebiotic world? And second, how was this directing force—could occur stochastically [4]. A tri-
bias sustained and propagated to give us the biological vial example is that any collection of an odd number
world of single chirality that surrounds us? of enantiomeric molecules has, by definition, broken
‘Symmetry breaking’ is the term used to describe symmetry. Fluctuations in the physical and chemical
the occurrence of an imbalance between enantiomeric environment could result in transient fluctuations in
molecules. This imbalance is traditionally measured the relative numbers of left- and right-handed mol-
in terms of the enantiomeric excess, or ee, where ee ¼ ecules. However, any small imbalance created in this
(R – S)/(R þ S) and R and S are concentrations of way should average out as the racemic state unless
the right and left-hand molecules, respectively. Propo- some process intervenes to sustain and amplify it.
sals for how an imbalance might have come about may Thus, whether or not the imbalance in enantiomers
be classified as either terrestrial or extraterrestrial, and came about by chance, arising on the Earth or else-
then subdivided into either random or deterministic. where, an amplification mechanism remains the key
Evidence of small enantiomeric excesses in amino to sustaining enantioenrichment. A description of
acids found in chondritic meteor deposits [2] allows mechanisms for how this imbalance might be ampli-
the hypothesis that the initial imbalance is not of our fied is the main subject of this review.
Theoretical models for how a small initial imbalance
in enantiomer concentrations might ultimately be
*blackmond@scripps.edu turned into the subsequent production of a single enan-
One contribution of 17 to a Discussion Meeting Issue ‘The chemical tiomer have been discussed for more than half a century
origins of life and its early evolution’. [5,6], but only more recently have experimental studies
2878 This journal is q 2011 The Royal Society
 The origin of biological homochirality D. G. Blackmond 2879

3L:2D

4L:2D

6L:2D

= enantiomer autocatalysts
= pair selected for ‘mutual antagonism’
= deactivated enantiomers 10 L : 2 D

Figure 1. Schematic of the Frank model for the evolution of homochirality based on autocatalytic replication and mutual
antagonism of enantiomers.

begun to address this question directly. In the past two figure 1, the self-production of enantiomers will
decades several distinct models with strikingly different cause the ratio of L : D to grow as long as an initial
features have emerged. These models draw upon both imbalance was present at the beginning of the process.
the chemical and the physical behaviour of chiral mol- Together, autocatalysis and mutual antagonism propa-
ecules, and they may be classified according to their gate and amplify the imbalance in enantiomers. The
relative emphasis on kinetics versus thermodynamics of only catch is that the smaller the initial imbalance,
the processes involved. ‘Far-from-equilibrium’ models the greater the number of L and D molecules lost in
involving autocatalytic chemical reactions or crystalliza- the deactivation process before significant enantio-
tion processes lie at one end of the spectrum. At the enrichment can occur. If the substrate pool is large
other end, a model based on equilibrium phase behav- enough, however, the process can be sustained, and
iour proposes a physical explanation. And in-between the selectivity of autocatalytic production of one
lies a model that invokes an interplay between thermo- enantiomer will eventually dominate.
dynamics and kinetics to explain how a combination of More than 40 years later, the first experimental
physical and chemical processes can drive a system of proof of this concept was found when Soai et al. [8]
near-equal numbers of enantiomeric molecules to the reported the autocatalytic alkylation of pyrimidyl alde-
left or to the right. hydes with dialkylzincs (scheme 1), in which the
reaction rate is accelerated by addition of catalytic
amounts of its alcohol product. In addition, and
2. AUTOCATALYSIS most strikingly, this reaction was shown to yield the
More than 60 years ago, Frank developed a mathemat- autocatalytic product in very high ee starting from a
ical model for an autocatalytic reaction mechanism for very low ee in the original catalyst.
the evolution of homochirality. The model is based on Since this initial discovery, Soai’s group has gone
a simple idea: a substance that acts as a catalyst in its on to present remarkable further observations of asym-
own self-production and at the same time acts to sup- metric amplification in the reaction that now bears his
press synthesis of its enantiomer enables the evolution name. Enantiomeric excesses as high as 85 per cent
of enantiopure molecules from a near-racemic mixture. were reported for a reaction initiated with an initiator
The experimental challenge to discover a reaction with produced at 0.1 per cent ee from exposure to circularly
these features was posed in the last sentence of this polarized light [9]. Asymmetric amplification has also
purely theoretical paper: ‘A laboratory demonstration been observed for the reaction initiated by inorganic
may not be impossible’ [6,7]. chiral materials, such as quartz [10]. Most recently,
Frank’s proposal serves to highlight the critical role Soai has shown that the reaction may be selectively
played by an inhibition mechanism in autocatalytic triggered solely by the minute mirror-image difference
models for the evolution of homochirality. Figure 1 provided by 12C/13C carbon isotope chirality of an
illustrates this point using an example of a small initiator molecule [11], demonstrating that the reac-
group of L and D enantiomers that act as autocatalysts tion needs only an extremely small nudge to direct it
in an unlimited pool of substrate molecules. Each consistently to the left or to the right.
enantiomer is capable of reproducing itself in a reac- Soai’s observations continued to amaze and con-
tion with a substrate molecule. In addition, there is found the community for several years before the
‘mutual antagonism’ between L and D such that first mechanistic rationalization of the reaction was
when they react together, both become deactivated reported by Blackmond et al. in 2001 [12]. A kinetic
and lose their capacity to self-replicate. As shown in model was developed based on detailed experimental
Phil. Trans. R. Soc. B (2011)
2880 D. G. Blackmond The origin of biological homochirality

autocatalysis

O Zn
O O Zn
N
N H R N N
Zn(iPr)2
R N catalytic R N
low ee
1 2 3a
3b
high ee
Scheme 1. The Soai autocatalytic reaction, where the product catalyses its own formation. The –CH3 group in the pyrimidyl
aldehyde may be replaced with other groups such as alkynyl groups.

measurements of the autocatalytic rate profiles of the 1.0

Soai reaction. The kinetic model rationalizes asym-
metric amplification based on an extension of 0.8
Kagan’s model for nonlinear effects in catalytic
reactions [13], that is, cases where the reaction pro-
0.6
product ee
duct ee does not scale linearly with the catalyst ee.
Such behaviour may ensue when the catalyst mol-
ecules aggregate to form higher order species, such 0.4
as dimers. Blackmond and Brown’s studies found
that the Soai reaction R and S products form a stochas- 0.2
tic distribution of homochiral and heterochiral dimers,
with essentially no stereochemical bias between the
0 0.2 0.4 0.6 0.8 1.0
dimers, and that the heterochiral dimer is inactive as
a catalyst. Because each homochiral dimer catalyst fraction conversion
produces more of itself in autocatalysis, and because Figure 2. Product ee as a function of reaction progress in
mutual antagonism allows the minor enantiomer to the Soai reaction of scheme 1 for reactions catalysed by
be siphoned off as an inactive heterochiral dimer (ser- 10 mol% of the reaction product with an initial ee of 6
ving the role of ‘mutual antagonism’ in the Frank and 22% [14]. Prediction of the Blackmond –Brown kin-
model), catalyst concentration increases, and rela- etic model (solid blue lines) and experimental values
tive concentration of the two homochiral dimers from chiral chromatographic analysis (filled magenta
changes, with reaction turnover. The kinetic model circles).
independently predicts both the temporal degree of
asymmetric amplification, confirmed by compositional
analysis, as well as the relative concentrations of the his tweezers), and there is no direct molecular inter-
catalyst species, confirmed by nuclear magnetic reson- action between D and L molecules [16]. These types
ance spectroscopy, as shown in figure 2 [14]. The of compounds are illustrated schematically in figure 3.
ultimate product ee that may be achieved in such an The type of crystal a chiral molecule forms in the
autocatalytic reaction is limited only by the size of solid phase is a fundamental property of that molecule
the substrate pool. This model demonstrates that at a given temperature and pressure. Racemic com-
effective amplification of ee in autocatalysis depends pounds are more prevalent than conglomerates by ca
less on sophisticated stereoselection and more on 10 : 1 on the planet Earth, including all but two of the
higher relative activity for the homochiral dimers, 19 proteinogenic amino acids that are chiral (the
repeated over many autocatalytic cycles [15]. 20th, glycine, is an achiral molecule). We discuss
models for homochirality based on each of these types
of crystal solids.
3. PHYSICAL MODELS
Physical models for homochirality invoke the physical
phase behaviour of chiral solids in dynamic inter- 4. ‘CHIRAL AMNESIA’ MODEL
change with their solution-phase molecules. The two A model describing a process for the evolution of
main types of crystals formed by chiral molecules are single chirality in the solid phase is based on landmark
(i) racemic compounds, where crystals contain a 1 : 1 work by Viedma, who first studied conglomerate crys-
ratio of D : L enantiomers; and (ii) conglomerates, tals of NaClO3, an inorganic, achiral salt. NaClO3
where each crystal is composed of molecules of a happens to crystallize as mirror-image crystals that
single enantiomer, and the crystals themselves are may be readily observed using circularly polarized
mirror images (as were those Pasteur separated with light [17]. In a now classic experiment, Viedma stirred
Phil. Trans. R. Soc. B (2011)
 The origin of biological homochirality D. G. Blackmond 2881

(a) (b)

L L D D D L L L

L L D D D D L D L L

L D D D L D L L L
L

Figure 3. Two types of crystalline solids formed by chiral compounds. Rectangles represent solid-phase enantiomeric mol-
ecules. (a) Conglomerates form separate crystals of each enantiomer; (b) racemic compounds form mixed crystals in a 1 : 1
ratio of the two enantiomers.

100
160°C
preferential dissolution
from small crystals
(D in this example) 50 90°C

solid phase ee (%)

solution phase racemization
L= D equalizes L and D
in solution 0
preferential re-accretion
onto large crystals
(L in this example)
–50

continual grinding 90°C

160°C
–100
0 5 10 15 20 25 30
time (days)
Figure 5. Evolution of solid-phase homochirality for aspartic
Figure 4. ‘Chiral amnesia’ process for the evolution of acid via solution-phase racemization. Energy input from
solid-phase homochirality for chiral molecules that form con- grinding the crystals in the presence of enhanced attrition
glomerate solids. In this example, an initial imbalance due to glass beads leads to a sigmoidal profile.
towards larger L crystals helps to drive the dissolution/
re-accretion process from D crystals to L crystals. The process
is aided by solution-phase racemization, which converts the
increasing the rate of re-accretion of solution-phase
‘excess’ dissolved D molecules to L molecules, equalizing NaClO3 onto existing crystals (figure 4). A key point is
the solution composition and enabling molecules that were that once a molecule of NaClO3 dissolves from a crystal,
formerly part of a D crystal to add as L molecules to L it no longer possesses chirality and it retains no memory
crystals. of the chiral form it previously exhibited as part of a
crystal. Solution-phase NaClO3 thus has no preference
for re-accreting to a left- or right-handed crystal. If
slurries containing equal amounts of left- and right- the system exhibits, by chance, a slight dominance
handed NaClO3 crystals in the presence of glass of large crystals of one hand, the preference for solu-
beads, which caused the solid particles to be finely tion molecules to add to larger crystals causes this
ground. Under these conditions, he observed that enantiomorphic solid to increase relative to its smaller
over time the system evolved inexorably and randomly mirror-image form.
to a single enantiomorphic solid. Evolution of solid-phase homochirality in this case
Viedma reasoned that the continual abrasion of the requires only an initial imbalance in the crystal size of
crystals enhanced both halves of the cycle of repetitive left versus right-hand crystals. The achiral solution
dissolution/crystallization that occurs in any dynamic phase serves as the conduit through which the molecules
solid-solution system. According to the Gibbs–Thom- from one hand of the crystal may readily become part of
son rule, small crystals dissolve more readily than large a crystal of the other hand, a feature that has been given
crystals, and large crystals grow more readily than the name ‘chiral amnesia’ (figure 5; [18,19]).
small ones. Attrition by glass beads produces a greater These results led many to consider a possible exten-
number of smaller crystals, whose increased dissolution, sion of this process from the achiral NaClO3 to
in turn, causes a slight supersaturation of NaClO3 in sol- intrinsically chiral molecules that form conglomerate
ution. Not sufficiently supersaturated to support solids. For these molecules, it was envisioned that
primary nucleation of new crystals, the system strives solution-phase racemization could play the role of the
to redress the balance between solid and solution by solution phase conduit, transferring molecules from
Phil. Trans. R. Soc. B (2011)
2882 D. G. Blackmond The origin of biological homochirality

O O
racemization
HO OH
OH HO
heat or
solid phase O NH2 heat/glass beads NH2 O solid phase

Scheme 2. Transformation of aspartic acid crystals from one enantiomorphic solid to the other via solution-phase racemiza-
tion. Mechanical or thermal energy input drives the dissolution/re-accretion process.

one crystal hand to the other by first interconverting Table 1. Eutectic ee values for a number of
them in solution. This process has been successfully proteinogenic amino acids, identified by their
demonstrated for intrinsically chiral molecules for an chemical structures and their three-letter names.
amino acid derivative [20] and for the proteinogenic
amino acid aspartic acid [21] (scheme 2). ser eeeut > 99% his eeeut = 93%
O O
HO OH N OH
NH2 NH NH2
5. CRYSTAL ENGINEERING MODEL
A model for the origin of biological homochirality for leu eeeut = 87% met eeeut = 85%
O O
amino acids that form racemic compounds has been
OH S
developed that provides solution-phase enantioenrich- OH
NH2 NH2
ment based on the different solubility of homochiral
and heterochiral crystals, as shown in figure 3b. phe eeeut = 88% ala eeeut = 60%
O O
When the numbers of enantiopure and D and L mol-
ecules are unequal, the minor enantiomer is present OH OH
NH2 NH2
in the solution phase only to the extent that it can dis-
solve from the D : L crystal. The lower the solubility of val eeeut = 46% thr eeeut = 0%
the D : L crystals, the more strongly ‘trapped’ in the O O
solid phase will be the minor enantiomer, and the OH HO OH
higher the resulting solution phase partitioning of NH2 NH2
the major enantiomer. This will be manifested as a
high solution phase ee, known as eeeut, and its value is
a characteristic of a particular compound. Several of concomitant rise in eeeut from 50 to more than 99 per
the proteinogenic amino acids form relatively insoluble cent ee, and D : L valine and phenylalanine each form
D : L crystals, and therefore, exhibit high eutectic ee
crystals incorporating fumaric acid; eeeut rose from 47
values, such as serine at greater than 99 per cent ee. and 88 per cent, respectively, to more than 99 per cent
This means that when a sample with nearly equal num- in both cases. The structure of the D : L compound of pro-
bers of D and L serine molecules is partially dissolved, a line with chloroform is shown in figure 7. Manipulation of
virtually enantiopure solution results. Table 1 provides the eutectic composition by additives may be thought of
eutectic values for a number of amino acids [22]. as an analogy to clathrate compounds, although here it
Enantioenrichment in solution is thus dictated by is the amino acid enantiomers themselves that are trapped
thermodynamics for chiral compounds that happen in the solvate–racemate structure, causing them to
to form relatively insoluble racemic compounds. dissolve much less readily.
This concept was first recognized by Morowitz [23] The finding that the ee of an amino acid in solution
40 years ago and was more recently elaborated by may be significantly enhanced via solvate formation
Klussmann et al. [22,24] and by Breslow & Levine enables an approach to enantioenrichment for a wide
[25]. Also Breslow & Cheng recently reported high range of chiral compounds. These studies suggest a
eutectic ee values for several nucelosides of prebiotic general and facile route to homochirality that may
importance [26]. A recent theoretical treatment have prebiotic relevance. Cycles of rain and evapora-
based on a two-dimensional lattice model successfully tion create pools containing a small initial imbalance of
predicts the ternary phase behaviour of amino acids amino acid enantiomers and appropriate hydrogen-
based on the interactions that stabilize the racemic bonding partner molecules that may form insoluble
crystal, providing molecular-level insight into the crystals. The resulting solution of enantioenriched mol-
observed enantiomer partitioning [27]. ecules might then serve as efficient asymmetric catalysts
Further experimental work has expanded this model or as building blocks themselves for construction of the
to include solution-phase enantioenrichment for chiral complex molecules required for recognition, replication
compounds with low intrinsic eeeut values by showing and ultimately for the chemical basis of life. [29].
that in many cases eutectic ee composition may be
‘tuned’ through incorporation of a variety of small, achiral
molecules into the solid-phase crystal structure via hydro-
gen-bonding [24,28]. If the incorporated molecule 6. COMPARISON OF PHYSICAL MODELS
reduces the solubility of the racemic crystal relative to Comparison of the chiral amnesia and crystal engin-
that of the enantiopure crystal, enhanced eutectic com- eering phase behaviour models for the origin of
position will result, as shown in figure 6. For example, D homochirality reveals that they are complementary
: L proline incorporates CHCl3 into its structure with a in many ways: the former produces solid-phase
Phil. Trans. R. Soc. B (2011)
 The origin of biological homochirality D. G. Blackmond 2883

(a) ca 50% ee (b) > 99% ee

D L D D D D

D L D D D D L D D D

L D L D D L D L D D

cosolvate molecule

Figure 6. Manipulation of eutectic ee value by formation of a solvate that reduces the solubility of the racemic compound.

(a) O(8) a (b)

C(6)
C(3) O(7)
C(2) c
N(1)
C(4) a
O(8A)
b
C(5)
d
0(7')
O(8') Cl(2)
O(7A) C(6')
c e
N(1') C(2') C(4') C(10)

Cl(1)
C(5')
C(3')
d Cl(3)
LD proline
O(8'A)
CHCl3

Figure 7. Crystal structure of LD proline incorporating one molecule of chloroform. (a) Five independent hydrogen bonds are
shown; (b) long range structure with proline enantiomers in blue and magenta, chloroform in black [24].

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