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The origin of chirality in nature Stephen Mason

Pasteur's discovery of the connection between optical activity and molecular chirality led him to suppose that the forces of nature are not mirror-symmetric. His conjecture is supported by the recent discovery that the weak interaction between fundamental particles does not conserve mirror-image equivalence, violating parity. As a consequence of the weak left-handedness of the electron, the L-amino acids and the r-peptides, predominant in the living world, are stabilized relative to their D-enantiomers. Stephen Mason presents this comprehensive review on the origin and current status of chirality as understood from a molecular optical activity viewpoint.

Substances with the same elemen- tary chemical composition but different physical properties, iso- mers, were a problem for chemists until a theory of molecular struc- ture was developed, from the 1860s on. A particular puzzle was the case of optical isomers, substances which appeared to be identical chemically and physically, except that, one form rotated the plane of polarized light to the right and another to the left, while a third form seemed to be optically- inactive, with no effect on polar- ized light. The phenomenon of isomerism was discovered by the isolation of two almost identical substances from the tartars deposi- ted by maturing wines. The major product, (+)tartaric acid, was found to be dextro-rotatory to polarized light, whereas the minor product, racemic or paratartaric acid, proved to be optically inac- tive. Mitscherlich, whose law of isomorphism (1819) correlated a similarity of crystal shape with an analogy in chemical composition, reported in 1844 that the sodium ammonium salts of (+)tartaric acid and of racemic acid are completely isomorphous and are identical in all respects otherwise, except opti- cal activity.

Louis Pasteur, while still a student in Paris (1843-1848), sus- pected that Mitscherlich's report

Stephen Mason is Professor of Chemistry, University of London, FJng's College, Strand, London WC2R 2LS, UK.

on the tartrates was incomplete. The pioneer work on optical activity had been carried out on quartz crystals, which occur natur- ally in two morphological forms. The two types of quartz are distinguished by minor crystal facets, the hemihedral facets, which form a left-handed screw pattern in one set and a right-handed pattern in the other (Fig. 1). At Cambridge in 1822, John Herschel had found that sections cut per- pendicular to the three-fold axis from any quartz crystal of the left- handed form are laevo-rotatory to polarized light whereas, corre- sponding sections from crystals of the right-handed set are invariably dextro-rotatory. In the light of Herschel's correlation, Pasteur set out to investigate the tartrate- racemate problem afresh.

Molecular dissymmetry On recrystallizing sodium-am-

monium racemate, Pasteur (1848) observed the formation of two similar sets of crystals, character- ized by the particular pattern of the hemihedral facets, as in the case of (+) and (-)quartz. One of the sets proved to be truly isomorphous with crystals of sodium-ammo- nium (+)tartrate in facet pattern and gave the same positive specific optical rotation in solution. The other set had a non-superposable mirror-image crystal form and gave a specific rotation of polar- ized light with the same magni- tude, but negative in sign. On acid treatment, the second crystal set

1986, El~--vier Science Pub l i she rs B.V., A m s t e r d a m 0165 - 6147/86/$02.00

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liberated (-)tartaric acid, the opti- cal isomer of the major naturally- occurring form. Accordingly, race- mic acid had to be regarded as a mixture of (+) and (-)tartaric acid and, thereafter, the term 'racemate' came to denote generally an optic- ally-inactive equimolar mixture of optical isomers.

Early last century the general view proposed by Ha/iy (1809) that a crystal and its constituent molecules are 'images of each other' in overall shape, led Pasteur to conclude that the individual molecules of [(+) and (-)]tartaric acid are structurally 'dissym- metric', related as non-superpos- able mirror-image forms, like the macroscopic hemihedral crystals of the corresponding sodium- ammonium salts. Later, Pasteur's term 'dissym~trie' for enantio- morphism (Greek enantios morphe, opposite shape), became generally supplanted by 'chirality', from the familiar analogy of the mirror- image relation between the left and the right hand.

Subsequently Pasteur conjec- tured that chiral molecules and enantiomorphous crystals are the product of universal dissymmetric forces in nature. Following the discovery by Faraday (1846) of magnetically-induced optical rota- tion in an otherwise inactive medium, flint glass, Pasteur grew normally-symmetric crystals in a magnetic field with the object of inducing enantiomorphous crystal forms. The solar system is dissym- metric, Pasteur supposed, on ac- count of the spin and orbital rotation of the planets. Regarding rotation as a dissymmetric force, he attempted to induce optical activity in synthetic products by running chemical reactions in a centrifuge, and to modify the optical activity of natural products by rotating the plants producing them with a clockwork mechan- ism. These experiments, and the negative results obtained, were reported by Pasteur only thirty years later, in a restatement of his belief in the universality of dis- symmetric forces.

Classical stereochemistry ~ Pasteur established the overall

shape-property of molecular han- dedness without a knowledge of molecular structure and, with a primary interest in microbiology after 1860, he was little concerned

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with the development of main- stream structural chemistry. Ke- kule extended his earlier (1858) one-dimensional theory of organic chain molecules, based upon the self-linkage of tetravalent carbon atoms, to the two-dimensional structural theory of aromatic sub- stances, predicting from the as- sumed regular hexagonal ring structure for benzene (1866) the number and the type of structural isomers subsequently found in the mono-, di- and poly-substitution reactions. Aliphatic organic chem- istry obtained little guidance from Kekule's structural theory. Even for simple cases, such as lactic acid, isolated in an optically-active form from muscle tissue and in an inactive form from sour milk, there appeared to be more isomers than could be accommodated by fiat- land molecular formulae.

The problem was taken up and solved independently in 1874 by Le Bel and van't Hoff. With the valencies of the carbon atom directed towards the vertices of a regular tetrahedron, the bonding of four different groups to the central atom gives two possible molecular structures, one being the non-superposable mirror- image of the other. The two structures correspond to the dex- tro-rotatory (+)form and the laevo- rotatory (-)enantiomer of a pair of optical isomers containing a single chiral centre, the 'asymmetric' carbon atom (Fig. 1).

The introduction of a second chiral centre into a molecule, equivalent to the first, gives three possible structures, consisting of an enantiomeric pair of optical isomers and an internally-com- pensated meso-form, as in the case of the tartaric acids. Two inequiva- lent chiral centres result in four possible structures, consisting of two enantiomeric pairs. A struc- ture from one pair was defined as 'diastereomeric' to a structure from the other pair, since the two structures lack the mirror-image relation of enantiomers, and the corresponding molecules differ in reactivity and physical properties.

Asymmetric, synthesis and biomolecular homochirality

The generalizations made by van't Hoff as to the number and types of stereoisomers resulting from multiple chiral centres were both tested and used as a guide by

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.&,->'- - t --- ,

Quartz crystals Right-hand

(1) M a c o c o p i c . . . . a ~ o ~ h o ~

C02- CO~-

/ r , \ / \ / I ~ \ / -~ \ / I .

! \

~ C,4 \ / I , , C ~ . . \ \

~ ~+

Lei~-handed Right-handed

(2) Molecular enantiomortc mucturu

Left-handed state Right-handed state

Direction of motion direction of motion

~ ~ t a z ~ w t t ~ ~ ~ x y m m u

F~g. 1. Three domains of chirality. (1) The minor crystal fa~ts follow a left- or right-handed sequence, viewed along the threefold crystal axis. (2) The NH3 +, C02. and CHs groups of alanine follow a left-handed or right-handed sequence, viewed with the bonded hydrogen atom remote from the observer. (3) The left- o¢ right-handed ch#ality of an electron, or any parUde, derives from the respective an~'paranel or paral~ relation between the linear momentum vector and the axial vector of the spin angular momentum.

T.

D

22

t .

D

Fig. 2. The time evolution of L and D enantiomers from an achiral or racemic substrate in an open flow-reactor system, with an autocatalytic production of each isomer and an enantiomedc cross-inhibition. The curves represent solutions of the kinetic equations:

d[L]/dt = (kl - k2[D])[L] and d[O]/dt = (kl ' - K2'[L])[D]

For case (I) the enantiomer concentrations [L] and [D] are equal, and the paired rate ' constants, kl and k l ; and k2 and k2; are identical, leading to a metastable racamic

production represented by the unique point, from which either branch of the homochiral production diverges, dependent upon chance perturbations. For case (2), with an inequality between the two rate constants of either pair, or between the enantiomer concentrations, the particular homochiral production branch with the advantage factor, (ztE/kT~ ~> 10 -~7, is selected. (Trefers to the absolute temperature and k to Boltzmann's constant.)

Emil Fischer in his invest igat ion of the sugar series. An aldohexose sugar wi th four inequivalent chiral centres has 16 stereoisomers, but the four asymmetric carbon atoms become two equivalent pairs in the corresponding dicarboxylic acid where the stereoisomerism is re- duced to four pairs of enant iomers and two meso-forras. The change from inequivalent to equivalent chiral centres, the chemical elimi- nat ion of the asymmetry at a chiral centre, and the ascent and descent of the sugar series, all served to support van ' t Hoff's guidel ines while correlating the configur- ations of the sugars.

At each stage in the ascent of the sugar series, it was observed that the introduct ion of the addi t ional chiral centre gave the two dia- stereomeric products in unequal yields. The el iminat ion of the chiral centre d is t inguishing a pair of diastereomers was found to be similarly selective, particularly when media ted by chiral catalysts. Fischer (1894) showed that D(--)~3- methylglucoside is hydrolysed by emulsin from bit ter almonds, but not by maltase from yeast, whereas D(+)0~-methylglucoside is cleaved by maitase, but not by emulsin. Moreover, nei ther of the corre- sponding L-glucosides are affected by either of the enzyme prepar- ations. On the basis of such Observations, Fischer (1894) pro-

posed that the reactions of chiral substances are governed by a 'key and lock' principle, the part icular product result ing from the best stereochemical fit being naturally selected.

Developments of Fischer's 'key and lock' pr inciple go far to account for the general adopt ion of only one of the two enantiomeric series of the sugars and of the 0~- amino acids in the biochemistry of l iving organisms. An economic and efficient turnover requires a homochiral biochemistry, just as efficient engineer ing depends up- on the use of r ight -handed homo- chiral screws. Fischer 's mechan- ism rests ul t imately on a dissym- metric force, however, or an equivalent source for the initial enant iomeric excess which subse- quently becomes amplif ied by the internal chiral discr iminat ion of biomolecular reactions. Moreover, the part icular handedness of the initial excess, L or D, or the specific chiral bias of the dissymmetr ic forces acting continuously, is ex- pected to correspond to the part i- cular biomolecular homochiral i ty sustained throughout the course of organic evolution, specifically the L-amino acids and the D-SUgars 2-4.

Parity non-conservation The polar forces which Pasteur

had taken to be intrinsically dissymmetr ic were shown by

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Pierre Curie (1894) to become chiral only in combinat ion, as in the case of a parallel or an antiparallel electric and magnetic field, produced by a r ight -handed or a lef t-handed helical charge displacement, respectively. The chiral combinat ion of the classical polar fields are even-handed, how- ever, and they have no inherent discr iminat ion between enantio- meric structures on a time and space average. Wigner ' s principle of pari ty-conservat ion (1927) held that the forces of nature are symmetric to a space-inversion, or an equivalent mirror-reflection.

Developments from the Ruther- ford-Soddy (1904) theory of the spontaneous t ransmutat ion of the radioactive elements led to the discovery of two new natural forces, the strong and the weak nuclear interaction, media t ing 0c- and B-decay, respectively. An accumulation of anomalies in ele- mentary particle physics led Lee and Yang (1956) to conclude that mirror- image symmetry is not a proper ty of the weak nuclear interaction. A consequence of the proposed pari ty violation, the asymmetric B-decay of radionucle- ides, was soon observed in the decay of 6°Co to 6°Ni with the emission of a ~-electron and in the corresponding antiparticle emis- sion of a ~-positron from the t ransmutat ion of SSCo to SSFe. The asymmetry found showed the electron to possess an intr insic left- handedness and the posi tron an inherent r ight -handedness from the preferred relation, antiparaUel and parallel respectively, between the directions of the spin axis and the l inear momentum (Fig. 1). The preference is proport ional to the ratio of the velocity of the particle, or antiparticle, to the speed of light.

The weak nuclear interactions init ially s tudied involve charge changes, as in ~-radioactivity. An addit ional and more significant weak neutral current interaction, involving the massive neutral boson Z °, detected at CERN in 1983, together with its charged counterparts, W + and W- emerged from the unification of the electro- magnetic with the weak nuclear interaction during the 1960s. The unif ied electroweak interaction violates pari ty through the electro- magnetic interaction, which pri- mari ly governs the b ind ing of

TIPS - January 1986

electrons to the nucleus in an atom and the bonding of the atoms in a molecule. Furthermore, the elec- troweak interaction does not vanish in the non-relativistic limit of small particle velocities, and parity violating effects are expec- ted in the normal stationary states of an atom or molecule.

The main atomic and molecular expectations from the electroweak interaction are, firstly, universal optical activity and secondly, a difference between the electronic b ind ing energy of two enantio- meric molecules in either a station- ary or a transition state. The universal optical activity arising from the electroweak interaction is the more important for the heavier atoms, and high sensitivity polar- ization-rotation studies of thal- lium, lead and bismuth atoms in the gas phase give an optical rotation with the correct sign and order of magnitude s'6.

The electroweak interaction in chiral molecules gives rise to a parity-violating shift of the elec- tronic b ind ing energy, Epv, which is positive for one isomer and negative for its enantiomer. The energy shift, Epv, like the optical activity, is dependent, not only upon the overall stereochemical configuration, but also upon the detailed molecular conformation. Ab- in i t io calculations for the two main regular conformations of the proteins, the (x-helix and the ~- sheet conformation, indicate that the polypeptides based upon the naturally occurring L-amino acids are stabilized relative to the cor- responding D-enantiomers by some 10-14j mo1-1 per peptide unit. For the conformation preferred in aqueous solution, the L-isomer is similarly the more stable of the two alanine enantiomers (Fig. 1), as for the other (x-amino acids. Further- more, the parent isomer of the naturally occurring series of D- sugars, D(+)glyceraldehyde is more stable than its L-enantiomer, again by some 10-14J mo1-1. In each case, the parity-violating energy difference between the enantio- mers, AEpv, is very small relative to the thermal energy, kT. The advan- tage factor, given by the ratio, (AEp~/kT), has the approximate

value of 10 -17 , which is equivalent to an enantiomeric excess of some 106 molecules of the L-polypeptide, or the L-amino acid, or the D-triose, per mole of the corresponding racemate in thermodynamic equi- l ibrium at ambient temperatures 7.

Chiral symmetry breaking Although very small, the en-

antiomeric energy differences for the (x-amino acids and the poly- peptides due to the electroweak interaction have a magnitude suf- ficient to break the chiral symme- try of open, non-equi l ibr ium, racemic reaction systems. Accord- ing to the mechanism of Frank 8, an open system in which each optical isomer autocatalyses its own pro- duction from an achiral substrate and competitively inhibi ts the propagation of its enantiomer, remains stable so long as the input of achiral substrate remains small, thereby producing a racemic out- put. When the substrate input is increased, a critical point is rea- ched where the racemic process becomes metastable and the sys- tem switches over to homochiral production, adopting either the L- or the D-channel, dependent upon chance fluctuations. The presence of even a small chiral perturbation at the critical point determines the particular homochiral production channel adopted, the parity violat- ing energy differences between the enantiomers of the (x-amino acids being adequate 9 (Fig. 2).

The small chiral perturbation required for the transition to homochiral production by the Frank mechanism is not neces- sarily internal to the racemic reaction system. The universality of the electroweak interaction implies a minor enantiomeric discrimination in the geochemis- try of the prebiotic period, provid- ing optically-enriched chiral in- organic catalysts and templates. The terrestrial distr ibution of quartz crystals, for example, i sno t wholly racemic. Over a collection of samples, totalling 16807 crys- tals, a 1% enantiomeric excess of ( - )quar tz is recorded, the excess being common to all localities sampled, in the Americas, Europe

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and Asia TM. [] [] []

It has been argued that bio- organic optical purity was achie- ved substantially by a mixed mineral-organic economy in a protobiotic period. Grounds for the proposal are that the formation of stereoregular chiral biopoly- mers, such as the poly-D-ribo- nucleotides or the poly-L-peptide (x-helix, which proceed efficiently with the appropriate optically- pure monomer, are specifically and severely inhibi ted by the enantiomeric monomer in an op- ticaUy-impure or racemic sub- strate 11. Furthermore, catalytic lay- ered alumino-silicates related to the chiral kaolinites are found to self-replicate with fidelity over several generations, retaining their organic catalytic properties, from aqueous solutions which are not matched in chemical composi- tion 12,13.

R e f e r e n c e s 1 The foundation of classical stereo-

chemistry and the physical basis of optical activity and chiral differentiation are discussed by Mason, S.F. (1982) Molecular Optical Activity and the Chiral Discriminations Cambridge University Press, Cambridge

2 Bonnet, W. A. (1972) in Exobiology (Ponnamperuma, C., ed.), pp. 170-234, North Holland, Amsterdam, London and New York

3 Miller, S. L. and Orgel, L. E. (1974) The Origins of Life on the Earth p. 171, Prentice-Hall, Englewood Cliffs

4 Ulbricht, T. L. V. (1981) Origins Life 11, 55-70

5 Emmons, T. P., Reeves, J.M. and Forston, E. N. (1983) Phys. Rev. Lett. 51, 2089-2092

6 Emmons, T. P., Reeves, J.M. and Forston, E. N. (1984) Phys. Rev. Lett. 52, 86

7 Mason, S. F. and Tranter, G. E. (1985) Proc. R. Soc. London, Ser. A397, 45--65

8 Frank, F. C. (1953) Biochim. Biophys. Acta 11, 459--463

9 Kondepudi, D. K. and Nelson, G.W. (1985) Nature (London) 314, 438--441

10 Palache, C., Berman, H. and Frondel, C. (1962-1965) Dana's System of Mineralogy 7th edn., Vol. III, p. 16, John Wiley, New York

11 Joyce, G. J., Visser, G. M., van Boeckel, C. A. A., van Boom, J. H., Orgel, L. E. and Van Westrenen, J. (1984) Nature (London) 310, 602--604

12 Weiss, A. (1981) Angew. Chem. Int. Ed. Engl. 20, 850--860

13 Calms-Smith, A. G. (1985) Sci. Am. 252, No. 6, 74--82