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The Origin of Biological Homochirality

Donna G. Blackmond

Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037

Correspondence: [email protected]

The single-handedness of biological molecules has fascinated scientists and laymen alikesince Pasteur’s first painstaking separation of the enantiomorphic crystals of a tartrate saltmore than 150 yrago. More recently, a number of theoretical and experimental investigationshave helped to delineate models for how one enantiomer might have come to dominate overthe other from what presumably was a racemic prebiotic world. This article highlightsmechanisms for enantioenrichment that include either chemical or physical processes, ora combination of both. The scientific driving force for this work arises from an interest inunderstanding the origin of life, because the homochirality of biological molecules is asignature of life.

INTRODUCTION

Homochirality as a Signature of Life

For centuries, symmetry concepts have fasci-nated scientists as well as artists, mathe-

maticians and writers, laymen and children.The property of chirality—nonsuperimposableforms that are mirror images of one another, asare left and right hands—is manifest in bothmolecular and macroscopic objects As earlyas 1874, and a quarter century after Pasteurshowed that salts of tartaric acid exist as mirrorimage crystals, van’t Hoff and Le Bel independ-ently postulated the existence of chiral mole-cules (Heilbronner and Dunitz 1993) (Fig. 1).Chirality held Alice’s attention as she ponderedthe macroscopic world she glimpsed throughthe looking glass, and her musings over whetherlooking-glass milk would be good to drink

presaged our quest to understand the molecularimportance of chirality.

The two forms of a chiral molecule, calledenantiomers, have identical physical and chem-ical properties, but they manner in which eachinteracts with other chiral molecules may be dif-ferent, just as a left hand interacts differentlywith left- and right-hand gloves. Chiral mole-cules in living organisms in Nature exist almostexclusively as single enantiomers, a propertythat is critical for molecular recognition andreplication processes and would thus seem tobe a prerequisite for the origin of life. Yet leftand right-handed molecules of a compoundwill form in equal amounts (a racemic mixture)when we synthesize them in the laboratory inthe absence of some type of directing template.

The fact of the single chirality of biologi-cal molecules—exclusively left-handed amino

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acids and right-handed sugars—presents uswith two questions: First, what served as theoriginal template for biasing production ofone enantiomer over the other in the chemicallyaustere, and presumably racemic, environmentof the prebiotic world? And second, how wasthis bias sustained and propagated to give usthe biological world of single chirality that sur-rounds us?

Short of constructing a Time Machine, wehave no way of elucidating precisely the chain ofevents that led to life on earth today. What wemay do instead is highlight the modern experi-mental and theoretical work that has attemptedto probe these questions. After a brief discus-sion of the first question, this review focuses pri-marily on the second of the two questions raisedearlier: the discussion of plausible mechanismsfor the evolution of molecular homochirality asexemplified by the D-sugars and L-amino acidsfound in living organisms today.

BACKGROUND

How It All Got Started: Chance versusDeterminism

“Symmetry breaking” is the term used todescribe the occurrence of an imbalancebetween left and right enantiomeric molecules.This imbalance is traditionally measured interms of the enantiomeric excess, or ee, whereee ¼ (R2S)/(R þ S) and R and S are concen-trations of the right and left hand molecules,respectively. Proposals for how an imbalancemight have come about may be classified aseither terrestrial or extraterrestrial, and thensubdivided into either random or deterministic

(sometimes called “de facto” and “de lege”respectively). Evidence of small enantiomericexcesses in amino acids found in chondriticmeteor deposits (Pizzarello 2006) (see Zahnleet al. 2010) allows the hypothesis that the initialimbalance is not of our world (although it begsthe question of where and how it did originate).Discussions of how an imbalance could haveoriginated here on earth often debate the ques-tion of whether life was preordained to be basedon D-sugars and L-amino acids or whether thishappened by chance, implying that a life formbased on the opposite chirality might havebeen just as likely at the outset. Here, physicsenters the picture: the discovery of parity viola-tion and the elaboration of one of its conse-quences, that the two enantiomers have a verysmall energy difference between them, ledmany to consider the implications for biologi-cal homochirality (Quack 2002). Quantitativeestimates of this energy difference have beenmade and revised in the intervening years, butit is clear that it is very, very small; whereasexperimental and theoretical work is ongoing,and the question is not yet settled, a relationshipbetween biological homochirality and parityviolation is not yet supported by experimentalfindings.

Proponents on the “chance” side of thisquestion point out that absolute asymmetricsynthesis—defined as the production of enan-tiomerically enriched products in the absenceof a chemical or physical chiral directingforce—could occur stochastically (Mislow2003). A trivial example is that any collectionof an odd number of enantiomeric moleculeshas, by definition, broken symmetry. Fluctua-tions in the physical and chemical environmentcould result in transient fluctuations in therelative numbers of left- and right-handedmolecules. However, any small imbalancecreated in this way should average out as the ra-cemic state unless some process intervenesto sustain and amplify it. Thus, whether ornot the imbalance in enantiomers came aboutby chance, arising on earth or elsewhere, anamplification mechanism remains the keyto increasing enantiomeric excess and ulti-mately to approaching the homochiral state.

HH

CH3 CH3

NH2H2N

HOOCCOOH

Figure 1. The two mirror-image enantiomers of theamino acid alanine.

D.G. Blackmond

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A description of mechanisms for how thisimbalance might be amplified is the main sub-ject of this review.

Amplifying the Imbalance

Theoretical models for how a small initialimbalance in enantiomer concentrations mightultimately be turned into the subsequent pro-duction of a single enantiomer have beendiscussed for more than half a century (Frank1953; Calvin 1969), but only more recentlyhave experimental studies begun to addressthis question directly. In the past two decadesseveral distinct models with strikingly differentfeatures have emerged, leading to the commentthat scientists are now “spoilt for choice” (Ball2007) among possible explanations for howone enantiomer came to dominate over theother in biological molecules. These modelsdraw on both the chemical and the physicalbehavior of chiral molecules, and they may beclassified according to their relative emphasison kinetics vs. thermodynamics of the processesinvolved. “Far-from-equilibrium” models in-volving autocatalytic chemical reactions orcrystallization processes lie at one end of thespectrum. At the other end, a model based onequilibrium phase behavior proposes a physicalexplanation. And in between lies a model thatinvokes an interplay between thermodynamicsand kinetics to explain how a combination ofphysical and chemical processes can drive a sys-tem of near-equal numbers of enantiomericmolecules to the left or to the right.

CHEMICAL MODELS

Homochirality via Autocatalysis

More than 60 yr ago, Frank developed a mathe-matical model for an autocatalytic reactionmechanism for the evolution of homochirality.The model is based on a simple idea: a substancethat acts as a catalyst in its own self-productionand at the same time acts to suppress synthesisof its enantiomer enables the evolution of enan-tiopure molecules from a near-racemic mix-ture. The experimental challenge to discover a

reaction with these features was posed in thelast sentence of this purely theoretical paper:“A laboratory demonstration may not beimpossible” (Frank 1953; Wynberg 1989).

Mutual Antagonism

Frank’s proposal serves to highlight the criticalrole played by an inhibition mechanism in auto-catalytic models for the evolution of homochir-ality. Figure 2 illustrates this point using anexample of a small group of L and D enantiomersthat act as autocatalysts in an unlimited pool ofsubstrate molecules. Each enantiomer is capableof reproducing itself in a reaction with a sub-strate molecule. In addition, there is “mutualantagonism” between L and D such that whenthey react together, both become deactivatedand lose their capacity to self-replicate. Theoriginal pool shown in Figure 2 has an imbal-ance of one extra L molecule compared withthe total number of D molecules, or 3:2 forthis simple example. Let’s say that one L andone D meet by chance and deactivate, whereasthe remaining molecules feed on the pool ofsubstrate and reproduce themselves. The activepool of enantiomers has now become 4:2.When these same processes repeat, the activepool becomes 6:2, then, then 10:2, and so on.One L and one D enantiomer are paired off ineach mutual antagonism event, and hence theself-production of enantiomers will cause theratio of L:D to grow as long as an initial imbal-ance was present at the beginning of the process.Together, autocatalysis and mutual antagonismpropagate and amplify the imbalance in enan-tiomers. The only catch is that the smaller theinitial imbalance, the greater the number of L

and D molecules lost in the deactivation processbefore significant enantioenrichment can occur.If the substrate pool is large enough, however,productivity can remain high, and the selectiv-ity of autocatalytic production of one enan-tiomer will eventually dominate.

Proof of Concept

This model might be considered trivial, andno experimental system is known to follow the


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process in Figure 2. But Frank’s understatedexhortation to experimental chemists to dis-cover an autocatalytic reaction with these keyfeatures captivated several generations of chem-ists. More than forty years later, the first exper-imental proof of this concept was found whenSoai and coworkers reported the autocatalyticalkylation of pyrimidyl aldehydes with dialkyl-zincs (Soai et al. 1995) (Scheme 1), in whichthe reaction rate is accelerated by addition ofcatalytic amounts of its alcohol product. In

addition, and most strikingly, this reaction wasshown to yield the autocatalytic product invery high enantiomeric excess starting from avery low enantiomeric excess in the originalcatalyst.

Since this initial discovery, Soai’s group hasgone on to present remarkable further observa-tions of asymmetric amplification in the reac-tion that now bears his name. Enantiomericexcesses as high as 85% were reported for a reac-tion initiated with an initiator produced at 0.1%

N

N

N

N

OH

H3C

H3C

A Z

2

CHO

N

NOH

R or S

Catalytic R or SZn

Autocatalysis

Low ee

High ee

H3C

Scheme 1. The Soai autocatalytic reaction, in which the product catalyzes its own formation. The –CH3 groupin the pyrimidyl aldehyde may be replaced with other groups such as alkynyl groups.

L L D

LL D

L D

D

L D

L

L D

L D

L D

L D

L D

L D

L D

LL D DL LL

D

D

D

L LL

L L L

L L L

L L L

L

10L : 2D

6L : 2D4L : 2D

3L : 2D

KEY

= enantiomer autocatalysts

= pair selected for “mutual antagonism”

= deactivated enantiomers

Figure 2. Schematic representation of the Frank model for the evolution of homochirality based on autocatalyticreplication and mutual antagonism of enantiomers.

D.G. Blackmond




ee from exposure to circularly polarized light(Shibata et al. 1998). Asymmetric amplificationhas also been observed for the reaction initiatedby inorganic chiral materials such as quartz(Soai et al. 1999). Most recently Soai has shownthat the reaction may be selectively triggeredsolely by the minute mirror-image differenceprovided by 12C/13C carbon isotope chiralityof an initiator molecule (Kawasaki et al. 2009),demonstrating that the reaction needs only anextremely small nudge to direct it consistentlyto the left or to the right.

Mechanistic Corroboration of the FrankModel

Soai’s observations continued to amaze andconfound the community for several yearsbefore the first mechanistic rationalization ofthe reaction was reported by Blackmond andBrown in 2001 (Blackmond et al. 2001). Akinetic model was developed based on highlyaccurate in-situ measurements of the reaction’sprogress. What’s more, the kinetic model inde-pendently predicted both the temporal degreeof asymmetric amplification, confirmed bycompositional analysis, as well as the relativeconcentrations of the catalyst species, con-firmed by NMR spectroscopy. Figure 3 showshow the kinetic model compares with experi-mental data for asymmetric amplification inthe Soai reaction performed with two differentinitial catalyst ee values. This work showedthat the Soai reaction couples autocatalysiswith a form of “mutual antagonism,” thus evok-ing the main features of the Frank model, albeitin a more sophisticated chemical scenario.

The Blackmond/Brown model rationalizesasymmetric amplification in the autocatalyticSoai reaction based on an extension of Kagan’smodel for nonlinear effects in catalytic reactions(Girard and Kagan 1998), that is, cases in whichthe reaction product ee does not scale linearlywith the catalyst ee. Such behavior may ensuewhen the catalyst molecules aggregate to formhigher order species. The ML2 model describesthe formation of homochiral (RR and SS, Eqs. 1and 2) and heterochiral (SR, Eq. 3) dimers frommonomeric R and S molecules. The relative

concentration of these dimers depends on anequilibrium constant, KD (Eq. 4).

Rþ R!Khomo

! RR (1)

Sþ S!Khomo

! SS (2)

Rþ S!Khetero

! SR (3)

KD ¼½SR�

½RR� � ½SS� ¼Khomo

Khetero

� �2

(4)

Kagan’s model proposes that the two homo-chiral dimers act as enantiomeric catalysts, giv-ing opposite product ee values with identicalrate constants, whereas the heterochiral dimercatalyst produces racemic product and mayshow a rate constant different from that of thehomochiral dimer catalysts. Some degree ofasymmetric amplification will result for any sys-tem in which the heterochiral dimer catalyst isless active than its homochiral counterparts. Avalue of KD ¼ 4 indicates a stochastic or non-selective distribution of dimers, and largervalues of KD skew the distribution toward apreference for the heterochiral species.

Fraction conversion0

1

0.8

0.6

0.4

Pro

duct

ee

0.2

00.2 0.4

Kinetic model predictionExperimental data

0.6 0.8 1

Figure 3. Product enantiomeric excess as a functionof reaction progress in the Soai reaction ofScheme 1. Reactions catalyzed by 10 mol% of thereaction product with an initial ee of 6% and 22%(Buono and Blackond, 2003). Prediction of theBlackmond/Brown kinetic model (solid blue lines)and experimental values from HPLC analysis (filledmagenta circles).





The upper limit attainable of ee amplifica-tion attainable in a catalytic reaction followingthis model occurs for when the heterochiraldimer is inactive and is dictated by the magni-tude of KD: thus for a 1% ee catalyst showinga stochastic distribution of dimers, the maxi-mum amplification in the product ee is onlytwofold, to ca. 2% ee. Stronger amplificationof ee may be realized only by creating a specificstereochemical bias toward a stable, inactiveheterochiral dimer, that is, for systems showingKD values that are significantly higher than thatfor a stochastic distribution. For example, a 1%ee catalyst would require a KD value a million-fold higher than the stochastic distribution toapproach a perfectly enantioselective reaction.

Selection Without Bias

Although this model provides a means forasymmetric amplification, it presents a quan-dary for the prebiotic evolution of homochiral-ity. Today we can construct a strong bias inmodern asymmetric catalysts to provide a highKD value by drawing on the extensive naturalchiral pool of molecules for complex buildingblocks, but this resource would not have beenavailable to prebiotic molecules. The simplechiral molecules present in the prebiotic soupwould not necessarily be expected to formdimers with highly unequal homo/heterochiralstabilities. How could asymmetric autocatalystshave achieved the strong stereochemical bias indimer formation presumably needed to ensurestrong asymmetric amplification?

The simple answer is that they didn’t! Thebasic finding of Blackmond and Brown’s studiesis that the Soai reaction R and S products form astochastic distribution of homochiral and heter-ochiral dimers, with essentially no stereochem-ical bias between the dimers (KD ¼ 4), and thatthe heterochiral dimer is inactive as a catalyst.The key to how this allows an approach tohomochirality is provided by consideration ofbasic differences among catalytic reactions,which accelerate the formation of a speciesthat is not the same as the catalyst, and auto-catalytic reactions, in which the catalyst accel-erates its own formation. Because the catalyst

produces more of itself in autocatalysis, andbecause mutual antagonism allows the minorenantiomer to be siphoned off as an inactiveheterochiral dimer (serving the role of “mutualantagonism” in the Frank model), the relativeconcentrations of the two enantiomers is notfixed at its initial value, as it is in a static catalyticsystem. Instead, in an autocatalytic system fol-lowing this dimer model, catalyst concentrationincreases, and relative concentration of the twohomochiral dimers changes, with reaction turn-over. The ultimate product enantiomeric excessthat may be achieved in such an autocatalyticreaction is limited only by the size of the sub-strate pool, not by the magnitude of KD. Return-ing to our example of catalyst 1% ee with KD ¼

4, comparison with an autocatalyst with identi-cal initial ee and KD shows that the autocatalyticsystem approaches homochirality after just 5000cycles; strong robustness trumps mild intrinsicselectivity. Amplification of ee in autocatalysisrequires not sophisticated stereoselection butonly higher activity for the homochiral dimers,repeated over many autocatalytic cycles.

Homochirality: Chance Aided by Luck

Thus the dimer model provides an elegant andsimple solution to one mystery of the evolutionof homochirality (Blackmond 2006). If, as inthe Soai reaction, the relative dimer reactivitieshappen to give the edge to the homochiralspecies, amplification, and ultimately homo-chirality, is ensured even for nonselective dimerformation. Statistics (stochastic dimer forma-tion) and one stroke of luck (lower activity ofthe heterochiral dimer) are sufficient prerequi-sites to account for the evolution of our homo-chiral world today.

PHYSICAL MODELS

Kinetics versus Thermodynamics

The Soai autocatalytic reaction is essentiallyirreversible under the conditions used; the reac-tion proceeds faster as more product (catalyst!)is formed, as long as it continues to receive thenutrients it requires. In the time scale of the

D.G. Blackmond




laboratory, the system never approaches theequilibrium state that would allow the reversereactions to participate and ultimately erodeselectivity. Analogous “far-from-equilibrium”processes showing amplified enantioselectivityas described earlier for the Soai reaction havebeen observed in physical processes such asthe crystallization of molecules that form chiralsolids. In these cases, kinetics must win out overthermodynamics in order for homochirality toevolve. The interconnection between kineticsand thermodynamics is addressed further inour consideration of two additional modelsfor homochirality invoking the physical phasebehavior of chiral solids in equilibrium withtheir solution phase molecules. An intrinsic fea-ture of both of these models is the dominantrole of the equilibrium condition, in contrastto the “far from equilibrium” cases invokingeither chemical reactions and crystallizationprocesses discussed earlier. These phase behav-ior models are underpinned by the fundamentalconcepts of the Gibbs Phase Rule as articulatedby ternary phase diagrams of L þ D þ solvent.

Phase Behavior of Chiral Solids

Before discussing these two models in detail, itis instructive to review the types of solution-solid behavior commonly found for enantio-meric molecules such as amino acids (Jacqueset al. 1994). Chiral compounds crystallizemost commonly in one of two forms: (a) as aracemic compound, in which crystals contain a1:1 ratio of D:L molecules; or (b) as a conglomer-ate, in which each crystal is comprised of mole-cules of a single enantiomer, and the crystals

themselves are mirror images (as were thosePasteur separated with his tweezers), and thereis no direct molecular interaction between D

and L molecules. These types of compoundsare illustrated schematically in Figure 4. Thetype of crystal a chiral molecule forms in thesolid phase is a fundamental property of thatmolecule at a given temperature and pressure.Racemic compounds are more prevalent thanconglomerates by ca. 10:1 on planet Earth,including all but two of the 19 proteinogenicamino acids that are chiral (the twentieth, gly-cine, is an achiral molecule).

Eutectic Composition

When unequal numbers of molecules that formeither type of crystal solid are partially dissolvedin water, the Gibbs phase rule teaches us that thesolution composition at equilibrium is fixed atwhat is called the “eutectic composition.” Oneinteresting contrasting feature of the two typesof compounds is that for conglomerates, thissolution contains equal numbers of D and L

molecules, giving a eutectic eeeut ¼ 0, whereasracemic compounds will show a nonzero eeeut.This is easily rationalized by considering thesolubility characteristics of each type of com-pound.

Conglomerates

Because the separate D and L crystals of a con-glomerate are enantiomeric, they have identicalproperties, including solubility. A saturated so-lution of D crystals thus has the same solutionconcentration as does a saturated solution of L

Conglomerate Racemic compound

DD

D D D

D D D DLL L L

L L L

L L

D D DL L L

A B

Figure 4. Two types of crystalline solids formed by chiral compounds. Rectangles represent solid phaseenantiomeric molecules. (A) conglomerates form separate crystals of each enantiomer; (B) racemic compoundsform mixed crystals in a 1:1 ratio of the two enantiomers.





crystals. If a mixture of D and L crystals is allowedto equilibrate together, each enantiomorphicsolid shows its own (identical) solubility inde-pendently, and the solution phase at equili-brium will contain equal numbers of of D andL molecules, and twice as many in total as foreither system separately (Meyerhoffer 1904)This remains true even if the system containsan unequal number of D and L molecules intotal, as shown in Figure 5A.

Racemic Compounds

The equilibrium phase behavior for a speciesforming a racemic compound is more complex.For the case of an unequal total number of D andL molecules, mixed 1:1 D:L crystals form prefer-entially, pairing up with all of the minor enan-tiomer in the solid phase, and any moleculesof the excess enantiomer remaining in the solidphase form homochiral crystals, as shown inFigure 5B. Thus at equilibrium this system willcontain two separate solid phases, one enantio-pure, and one racemic, along with the solutionphase. The D:L mixed solid contributes equalnumbers of D and L molecules to the solutionaccording to its characteristic solubility, andthe enantiopure solid does the same with itsone enantiomer, according to its solubility.The solution composition at equilibrium willdepend on the relative solubilities of the pureand mixed crystals, with the result that the

solution will show a eutectic ee value some-where between 0 and 100% (Fig. 5B). This valueis a characteristic of the particular chiral com-pound and is not known a priori.

Enantiomer Partitioning

In both cases, as Figure 5 shows, conglomeratesand racemic compounds present in a nonrace-mic composition in equilibrium with a solventshow a partitioning of enantiomers betweenthe solution and solid phases that is dictatedby the characteristics of the type of solidformed. Solution ee does not equal solid phaseee, and neither value will be the same as theoverall ee. The models discussed later makeuse of this concept of phase partitioning in dif-ferent ways to provide enantioenrichment ineither the solid phase or the solution phase. Fig-ure 5 suggests that solution phase enantioen-richment might be the goal when racemiccompounds are considered, whereas a mecha-nism for solid phase enantioenrichment mightmake more sense for conglomerates. This isexactly what has been found, as the sections laterdescribe.

PHASE BEHAVIOR I

“Eve Crystal” Model for Conglomerates

It has been known for more than one hundredyears that certain achiral molecules such as

L

L L L LD DDL

L L L

LLLL

D

Conglomerate

A B

Racemic compound

D D

DD

D

D

D

DL

L

L

Figure 5. Depiction of equilibrium between chiral crystalline solids and their aqueous solution phases fornonracemic mixtures of enantiomers. Rectangles represent solid phase enantiomeric molecules; coloredletters represent solution phase molecules in equilibrium with the solid phases. The solution phasecomposition is known as the eutectic. (A) conglomerates show eeeut¼ 0; (B) racemic compounds shownonzero eeeut.

D.G. Blackmond




NaClO3 crystallize as chiral solids. Work fromthe late 19th century noted that these crystalli-zations often resulted in a formation of two sep-arate chiral solid phases (Kipping and Pope1898). Most often, equal amounts of left andright-handed crystals are formed, but undersome conditions the system breaks symmetryduring the crystallization. The most strikingexample of this phenomenon was reportednearly two decades ago by Kondepudi (Konde-pudi et al. 1990) who showed that when thecrystallization process was accompanied byrapid stirring, crystals of single chirality couldbe formed, randomly left-handed or right-handed in repeated experiments. This wasrationalized by considering the dynamics ofcrystallization: formation of the first crystals(primary nucleation) from a homogeneoussupersaturated solution is slower than the proc-ess of crystal growth by adding molecules tocrystals already formed (secondary nucleation).Under rapid stirring, the first crystal formed, or“Eve” crystal, may be broken by shear into thou-sands of smaller crystals of the same chiral form.These “daughter” crystals then grow rapidly bydrawing on solution molecules, and the solu-tion rapidly becomes depleted. If this occurs

more rapidly than formation of any new pri-mary crystals, a single chiral solid state mayresult (McBride and Carter 1991) (Fig. 6).This phenomenon bears resemblance to “far-from-equilibrium” autocatalytic reaction proc-esses such as the Soai reaction discussed earlierin this article.

PHASE BEHAVIOR II

Near Equilibrium Systems

Most recently, this NaClO3 system that has fas-cinated scientists since van’t Hoff ’s days wasback in the news with a report by Viedma(2005) of a remarkable experimental finding.Viedma’s experiment is not strictly a crystalliza-tion; it starts at what would be the end of atypical crystallization performed without therapid stirring and shear described earlier, sothat the system is equilibrated with an equalnumber of right- and left-hand crystals ofNaClO3 in saturated aqueous solution, as inFigure 6A. Under these conditions, no new crys-tals nucleate; the only processes occurring in theflask are the continual dissolution and reaccre-tion of NaClO3 molecules to and from existing

D

D

D

L

L

LL

L

Evecrystal

L

Slow primary nucleationof multiple crystals

Rapid secondary nucleation due toshear of first crystal formed

Rapid stirringNo stirring

A B

L LL L

L LLL

Figure 6. Crystallization from supersaturated solution of achiral molecules that form mirror enantiomorphicsolid crystals. (A) Without rapid stirring, equal quantities of left- and right-handed crystals are formed; (B)under rapid stirring conditions, all crystals are grown from the fragments of a single primary crystal (“Evecrystal”), resulting in formation of only one enantiomorph.





crystals, and these rates are balanced at equili-brium. No net change is expected, and that isexactly what has been found in such experi-ments for more than one hundred years.Viedma then added glass beads to the gentlystirred vial, which enhanced the attrition ofthe crystals as they stirred. What he observedunder these conditions is that the systemevolved from equal quantities of left- and right-handed crystals to a single enantiomorphicsolid. One chiral solid converted completely tothe other over time, in a random fashion, some-times to the left and sometimes to the right,with equal probability. The striking fact is thatthe system moved inexorably from an apparentequilibrium between two enantiomorphic solidstates to a single chiral solid state, simply by vir-tue of the application of mechanical energy viathe grinding of glass beads.

Viedma reasoned that the continual abra-sion of the crystals by stirring with smallglass beads enhanced both halves of the cycleof repetitive dissolution/crystallization thatoccurs at equilibrium. According to the Gibbs-Thomson rule, small crystals dissolve morereadily than large crystals. Attrition by glassbeads produces a greater number of smallercrystals, whose increased dissolution in turncauses a slight supersaturation of NaClO3 in so-lution. Not sufficiently supersaturated to sup-port primary nucleation, the system strives toredress the balance between solid and solutionby increasing the rate of reaccretion of solutionphase NaClO3 onto existing crystals. A keypoint is that once a molecule of NaClO3 dis-solves from a crystal, it no longer possesses chir-ality and it retains no memory of the chiral formit previously showed as part of a crystal.Solution-phase NaClO3 thus has no preferencefor re-accreting to a left- or right-handed crys-tal. What solution phase molecules do have,however, is a preference for adding to largercrystals over smaller ones, a phenomenonknown as Ostwald ripening. If, by chance, thesystem contains a predominance of large crys-tals of one hand, solution phase NaClO3 willpreferentially add to these crystals, and thequantity of this enantiomorphic solid willincrease relative to its mirror image form.

Chiral AMnesia

The mechanical energy imparted to the systemby the enhanced attrition thus triggers an over-all process that is cyclical: The action of the glassbeads truncates the Ostwald ripening process,continually breaking up crystals as they attemptto grow in size. The growth of the crystals occursin response to an increased concentration driv-ing force created by slight supersaturation insolution, which in turn is the result of dissolu-tion of small crystals created by the glass beadsbreaking up larger crystals. Evolution of solidphase homochirality in this case requires onlyan initial imbalance in the crystal size of left-versus right-hand crystals.

This proposed rationalization implies thatthe system never departs very far from equili-brium conditions and that system strives con-tinually to restore the balance between thephysical processes of dissolution and reaccre-tion. The key to the evolution of one chiral solidstate is the ability of an achiral solution phasemolecule to choose to add to either hand ofits solid phase crystals. The solution phaseserves as the conduit through which the mole-cules that form one hand of the crystal forgettheir solid-state chiral history and are free tochoose a new solid-state chiral destiny, a processthat has been given the name “chiral amnesia”(Blackmond 2007; Viedma 2007).

Extension to Chiral Molecules

These results led many to consider a possibleextension of this process from the achiralNaClO3 to intrinsically chiral molecules thatform conglomerate solids, but this concept facesan important challenge. A chiral molecule insolution equilibrium with its two separate enan-tiomorphic solid phases would not have theability to choose to add to either solid; aD-amino acid molecule may add only to aD-crystal, and an L-amino acid molecule to anL-crystal. Although this does not affect theGibbs-Thomson and Ostwald ripening proc-esses for dissolution and growth of crystals, con-version of crystals of one hand into the otherwould be frustrated without a process allowing

D.G. Blackmond




the molecules to forget their chiral signature insolution. However, organic chemists engaged inasymmetric synthesis know well—and are oftenthemselves frustrated by—solution reactions inwhich chiral molecules can be made to convertbetween their left and right forms, knownas racemization. Long considered a bane inorganic synthesis, solution-phase racemizationprovides the key to extending the Viedmamodel for homochirality to intrinsically chiralmolecules, as shown schematically in Figure 7.

This was successfully shown recently for anamino acid derivative (Noorduin at al. 2008),for the proteinogenic amino acid aspartic acid(Viedma et al. 2008) (Scheme 2), and for aMannich reaction product (Tsogoeva et al.2009).

The studies of aspartic acid revealed that theinexorable move to one homochiral solid couldbe accomplished in the absence of glass beads,simply by application of thermal energy ratherthan mechanical energy as the means to nudge

L = D

Solution phase

Continual grinding

Racemizationequalizes L and D

in solution

Preferential dissolutionfrom small crystals(D in this example)

Preferential re-accretiononto large crystals(L in this example)

Figure 7. “Chiral amnesia” process for the evolution of solid-phase homochirality for chiral molecules that formconglomerate solids. In this example, an initial imbalance toward 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, whichconverts the “excess” dissolved D molecules to L molecules, equalizing the solution composition and enablingmolecules that were formerly part of a D crystal to add as L molecules to L crystals.

OHHO

HO

NH2

OH

O

O NH2

O

OSolid phase

Heat orheat/glass beads

Racemization

Solid phase

L L

L L

D D

D D

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





the system away from equilibrium. The crystalee profiles lose the exponential shape theyshow under the grinding conditions (Fig. 8),suggesting that Ostwald ripening may allowmore extensive crystal growth when the energyinput is thermal rather than mechanical.

PHASE BEHAVIOR III

Thermodynamic Model forEnantioenrichment

The phase properties of chiral compounds dis-cussed earlier have been understood for morethan one hundred years. More recently, a modelfor the origin of biological homochirality basedon solution phase enantioenrichment of aminoacids that form racemic compounds has beendeveloped based on these concepts. It may berecognized from Figure 5B that in a heteroge-neous mixture that contains unequal numbersof enantiopure and D and L molecules, theminor enantiomer is present in the solutionphase only to the extent that it can dissolvefrom the D:L crystal. The lower the solubility ofthe D:L crystals, the more strongly “trapped” inthe solid phase will be the minor enantiomer,and the higher the resulting solution phase

partitioning of the major enantiomer, mani-fested as a high eeeut. Several of the proteino-genic amino acids form relatively insoluble D:Lcrystals and therefore show high eutectic eevalues. For example, serine’s eutectic occurs at.99% ee. This means that when a samplewith nearly equal numbers of D and L serinemolecules is partially dissolved, a virtuallyenantiopure solution results. Table 1 provideseutectic values for a number of amino acids(Klussmann et al. 2006).

Enantioenrichment in solution is thus dic-tated by thermodynamics for chiral compoundsthat happen to form relatively insoluble racemiccompounds. This concept was first recognizedby Morowitz (1969) 40 yr ago and was morerecently elaborated by Blackmond’s work prob-ing eutectic composition for a variety of aminoacids and other chiral compounds Klussmannet al. 2006), and by Breslow (Breslow and Levine2006) who recently also reported high eutecticee values for several nucelosides of prebioticimportance (Breslow and Cheng 2009). A recenttheoretical treatment based on a two-dimen-sional lattice model successfully predicts the ter-nary phase behavior of amino acids based onthe interactions that stabilize the racemic crys-tal, providing molecular level insight into theobserved enantiomer partitioning (Lombardoet al. 2009). These studies suggest a generaland facile route to homochirality that mayhave prebiotic relevance. Cycles of rain andevaporation establishing solid phase-solutionphase equilibrium in pools containing a smallinitial imbalance of amino acid enantiomerscould result in a solution of enantioenrichedmolecules that might then serve as efficientasymmetric catalysts or as building blocksthemselves for construction of the complexmolecules required for recognition, replicationand ultimately for the chemical basis of life.

Sublime Partitioning

The phase partitioning of enantiomers thatforms the basis of this model for solution phaseenantioenrichment might be expected to pre-dict other phase behavior of enantiomers(Blackmond and Klussmann 2007a). Indeed,

Time (days)

0

100

80

60

40

Sol

id p

hase

ena

ntio

mer

ic e

xces

s (%

)

20

010 20 30 40 50

WITHOUTattrition enhancement

WITHattrition enhancement

60

Figure 8. Evolution of solid-phase homochirality foraspartic acid via solution phase racemization. Energyinput from grinding the crystals in the presence ofenhanced attrition because of glass beads leads to asigmoidal profile (filled blue circles), whereas ther-mal energy input drives the process in a linear fashion(open symbols).

D.G. Blackmond




eutectic ee values correlate with fusion temper-ature for a number of amino acids. In addition,reports of enantioenrichment of amino acidsvia sublimation of enantioimpure D/L mixturesare also well correlated with the eutectic ee val-ues for amino acids: for example, the sublimatefrom serine is nearly enantiopure, whereas thatfrom threonine, which forms a conglomerate,gives 0% ee (Perry et al. 2007). Sublimate ee val-ues of 72%–89% were observed for leucine, inaccordance with it measured eutectic value of88% ee (Fletcher et al. 2007). Enantiomer parti-tioning via sublimation raises tantalizing specu-lation about amino acids in space and anextraterrestrial origin of enantioenrichment.

Crystal Engineering for Tuning Eutectics

Because eutectic ee is a characteristic property ofa compound, it would appear that enantioen-richment by this approach is limited to chiralcompounds such as serine that happen toshow high eutectic ee values. Thermodynamics

suggests that other amino acids, such as valinewith eeeut ¼ 47%, may be stuck with the handthat Nature has dealt. However, further workrevealed the exciting discovery of a route to so-lution phase enantioenrichment that may beachieved even for chiral compounds with lowintrinsic eeeut values. Eutectic ee compositionmay be “tuned” in many cases by through incor-poration of a variety of small, achiral moleculesinto the solid phase structure of amino acidcrystals via hydrogen bonding (Klussmannet al. 2007). The existence of cocrystals knownas solvates or polymorphs is well known, buteffects on solubility and the accompanyingimplications for solution phase enantioenrich-ment were not recognized, until Blackmond andcoworkers (Klussmann et al. 2007a) showed thatenhanced eutectic ee values may be obtainedin a number of such cases. If the incorporatedmolecule reduces the solubility of the racemiccrystal relative to that of the enantiopure crystal,enhanced eutectic composition will result, asshown in Figure 9. For example, D:L proline

Table 1. Eutectic ee values for a number of proteinogenic amino acids,identified by their chemical structures and their three-letter names.

O

O

O

O

O

O

O

O

OH

OH

OH

OH OH

OH

HO

OH

OH

HONH2

NH2

NH2

NH2NH2

NH2

NH2

NH2

S

NH

N

Ser His

MetLeu

eeeut > 99% eeeut = 93%

eeeut = 85%

Ala eeeut = 60%

eeeut = 87%

Phe eeeut = 88%

Thr eeeut = 0%Val eeeut = 46%





incorporates CHCl3 into its structure with aconcomitant rise in eeeut from 50% to .99%ee, and D:L valine and phenylalanine eachform crystals incorporating fumaric acid;eeeut rose from 47% and 88%, respectively,to .99% in both cases. The structure of theD:L compound of proline with chloroform isshown in Figure 10. Manipulation of the eutec-tic composition by additives may be thoughtof as an analogy to clathrate compounds,although here it is the amino acid enantiomersthemselves that are trapped in the solvate-race-mate structure, causing them to dissolve muchless readily.

The finding that the enantiomeric excess ofan amino acid in solution may be significantly

enhanced via solvate formation enables anapproach to enantioenrichment for a widerange of chiral compounds. A particularlyappealing feature of this model is that it is basedon an equilibrium mechanism, in contrast tothe far-from-equilibrium environment invokedin kinetically induced amplification via auto-catalytic reactions discussed earlier. Prebioticpools containing nearly racemic amino acidscould exist over long periods of time awaitingan influx of appropriate hydrogen-bondingpartner molecules to form solvates that helpprovide enantiopure amino acids in solutionswhere the chemical reactions leading to lifemight begin to occur (Klussmann and Black-mond 2007b).

L

LL

D

D D

D D D

DD L

cosolvate molecule

D D D

DDL

LD

LD D D D D

Ca. 50% ee

A B

>99% ee

Figure 9. Manipulation of eutectic ee value by formation of a solvate that reduces the solubility of the racemiccompound.

A B

Figure 10. Crystal structure of LD proline incorporating one molecule of chloroform. (A) five independenthydrogen bonds are shown; (B) long range structure with proline enantiomers in blue and magenta,chloroform in black (Klussmann et al. 2006).

D.G. Blackmond




CHALLENGES AND FUTURE DIRECTIONS

Homochirality First?

Amino acids and sugar molecules are produced assingle enantiomers in biological processes onearth today, and these molecules provide thebuilding blocks for homochiral polymers suchas peptide chains, RNA and DNA. However, itis far from certain that homochirality on themolecular level was required before nascent bio-polymers began to play a role in the growingchemical complexity that led to life. This leavesopen the possibility that the prebiotic molecularpool need not have been enantioenriched. It hasbeen suggested that in competition for growth,heterochiral chains containing both enantiomerswould readily give way to homochiral polymers(Wald 1957; Kuhn 1972, 2007), and thereforeselection of one hand of an amino acid over theother could have come with oligopeptides ratherthan at the molecular level (Zepk et al. 2002).However, such a scenario still needs to invoke amechanism—either chance or deterministic—for symmetry breaking of the mirror imagehomochiral polymer chains that would evolve.A plausible proposal is that partial enantioenrich-ment could have taken place at the molecularlevel, but that prebiotic amino acids and sugarsneed not to have evolved completely to singlechirality before the formation of the first biopol-ymer chains. The greater the pre-enrichment onthe molecular level, the more efficient would bethe construction of homochiral chains, but theburden of chiral selectivity might have beenshared as complexity increased.

The Future for Autocatalysis

The experimental conditions of the Soai reac-tion preclude it from being of direct prebiotic

importance, because it is unlikely that thedialkylzinc chemistry involved would thrive anaqueous, aerobic prebiotic environment. How-ever, the reaction has been particularly instruc-tive in helping understand how autocatalysiscoupled with inhibition could lead to a homo-chiral state. A number of experimental aspectsof the Soai autocatalytic reaction are still understudy, and a number of other theoretical kineticmodels have been proposed, but the Black-mond/Brown model remains the only proposalthat provides an adequate rationalization of theexperimental data for the Soai reaction (Black-mond 2004, 2006a). Most recently, reports byTsogoeva (Mauksch et al. 2007) of a purelyorganic reaction showing similar properties ofautocatalysis and amplification of ee (Scheme 3)have excited the community, because the chem-istry involved is much closer to what could beprebiotically plausible. Further work to under-stand the mechanism of this reaction is cur-rently underway in a number of laboratories.

Phase Behavior Models

Comparison of the chiral amnesia and crystalengineering phase behavior models for theorigin of homochirality reveal that they arecomplementary in many ways: the former pro-duces solid-phase homochirality whereas thelatter provides enantioenrichment of the solu-tion phase; the chiral amnesia model convertsone enantiomer to the other, whereas the crystalengineering model simply partitions the exist-ing molecules between phase. Chiral amnesiamay be applied only to molecules that formconglomerates, which means that only about10% of known chiral compounds are candidatesfor enantioenrichment by this model. On theother hand, about 85% of chiral compounds

+

N

O O

OO

MeOHN

OEt

Autocatalysiswith amplification of ee?

OEt

OMe

Scheme 3. Autocatalytic Mannich reaction reported by Tsogoeva.





might be amenable to the selective partitioningprovided by the crystal engineering model. Per-haps some combination of the two led to theinitial enantioenrichment of biologically rele-vant molecules. Both models provide reason-able prebiotic scenarios, and further work tounderstand the mechanism of enantioenrich-ment in each case is underway.

Where Do We Go from Here?

The pathway to life may be seen as a saga ofincreasing chemical and physical complexity(see, for example, Hazen 2010). The modernfield of “systems chemistry” (von Kiedrowski2005) seeks to understand the chemical rootsof biological organization by studying the emer-gence of system properties that may be differentfrom those showed individually by the compo-nents in isolation. The implications of the singlechirality of biological molecules may be viewedin this context of complexity. Whether or not wewill ever know how this property developed inthe living systems represented on Earth today,studies of how single chirality might haveemerged will aid us in understanding the muchlarger question of how life might have, andmight again, emerge as a complex system.

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March 31, 20102010; doi: 10.1101/cshperspect.a002147 originally published onlineCold Spring Harb Perspect Biol

Donna G. Blackmond The Origin of Biological Homochirality

Subject Collection The Origins of Life

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et al.Norikazu Ichihashi, Tomoaki Matsuura, Hiroshi Kita,

The Hadean-Archaean EnvironmentNorman H. Sleep

RibonucleotidesJohn D. Sutherland

An Origin of Life on MarsChristopher P. McKay

Characterize Early Life on EarthHow a Tree Can Help−−Deep Phylogeny

RandallEric A. Gaucher, James T. Kratzer and Ryan N.

Primitive Genetic PolymersAaron E. Engelhart and Nicholas V. Hud

Medium to the Early EarthCosmic Carbon Chemistry: From the Interstellar

Pascale Ehrenfreund and Jan Cami

Membrane Transport in Primitive CellsSheref S. Mansy

Origin and Evolution of the RibosomeGeorge E. Fox

The Origins of Cellular LifeJason P. Schrum, Ting F. Zhu and Jack W. Szostak

BiomoleculesPlanetary Organic Chemistry and the Origins of

Kim, et al.Steven A. Benner, Hyo-Joong Kim, Myung-Jung

From Self-Assembled Vesicles to ProtocellsIrene A. Chen and Peter Walde

the Origins of LifeMineral Surfaces, Geochemical Complexities, and

Robert M. Hazen and Dimitri A. Sverjensky

The Origin of Biological HomochiralityDonna G. Blackmond

Historical Development of Origins ResearchAntonio Lazcano

Earth's Earliest AtmospheresKevin Zahnle, Laura Schaefer and Bruce Fegley

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