Small Enantiomeric Excess Research Articles

Approaches to chemically modified enzymes as synthetic catalysts

Attempts to introduce new catalytic activities of potential use in synthetic transformations into enzyme active sites are described. Substitution of the naturally occurring zinc in carboxypeptidase A by several metals known to catalyse hydrogenation was investigated; a new protein characterised as a rhodium carboxypeptidase was isolated but it failed to show activity as a hydrogenation catalyst for the reduction of a series of dehydroamino acid amides. Horse liver alcohol dehydrogenase was investigated for its potential to act as an oxygen transferase via Lewis acid catalysis. A series of cyclohexenyl and phenylribosides together with new alkenyl(arenyl)oxymethylenoxyethanols was prepared for evaluation as substrates; in the course of this study, novel neighbouring group participation by the oxygen atom of a chloromethyl ether was observed. Although the binding of potential oxygen acceptors (alkenes and aromatic compounds) and oxygen donors (hydrogen peroxide and alkyl hydroperoxides) was demonstrated, oxygen transfer did not occur with the combinations investigated. In contrast to the failure of the above metalloenzymes to catalyse new reactions, papain modified at the active site sulfhydryl group by thiazolium salts and pyridinium salts was shown to exhibit reactions characteristic of the covalently attached cofactor. Thus the thiazolopapains acted as decarboxylation catalysts for pyruvate and, the pyridinopapains could be reduced to dihydropyridines which reduced electrophilic carbonyl substrates with small enantiomeric excess.

Enantioselectivity in a free-radical oxidation: measurement of small enantiomeric excesses

Partial conversion of 2-methyl-1-phenylpropan-1-ol into isobutyrophenone by the acyl aminoxyl radicals formed on oxidation of enantiomerically pure N-fenchelylbenzohydroxamic acid or its para-nitro derivative occurs with small but measurable enantioselectivity. This has been demonstrated using HPLC with diode-laser-based polarimetric detection to examine unchanged alcohol in the reaction mixtures.

Terrestrial and extraterrestrial sources of molecular homochirality

The unique chirality of biomolecules is reviewed, and the prebiotic requirement for the absolute chiral homogeneity of such molecules prior to their capability of self-replication is emphasized. Biotic and abiotic theories embracing both chance and determinate mechanisms which have been proposed for the origin of terrestrial chiral molecules are briefly summarized and evaluated, as are abiotic mechanisms for the subsequent amplification of the small enantiomeric excesses (e.e.s) in the chiral molecules which might be formed by such processes. While amplification mechanisms are readily validated experimentally and are potentially viable on the primitive Earth, it is concluded that all terrestrial mechanisms proposed for the origin of chirality have one or more limitations which make them either intrinsically invalid or highly improbable in the chaotic and turbulent environment of the prebiotic Earth. To circumvent these difficulties we have proposed an extraterrestrial scenario for the production of terrestrial chirality in which circularly polarized synchrotron radiation from the neutron star remnant of a supernova interacts with the organic mantles on interstellar grains, producing chiral molecules by the partial asymmetric photolysis of racemic constituent in the mantles, after which the interstellar grains with their enantiomerically enriched mantles are transported to Earth either by direct accretion or through cometary impact. At this point one of the known terrestrial e.e. enrichment mechanisms could promote the small extraterrestrially produced e.e.s. into the state of chiral homogeneity required for self-replicating biomolecules.

Amplification of chirality based upon the association of nucleic acid strands of opposite handedness

It is proposed that nucleotide strands of opposite handedness may strongly associate and thereby provide the key step of a mechanism for the amplification of a small enantiomeric excess in an initially near-racemic mixture of poly- or oligonucleotides. This hypothesis, if confirmed by experimentation, may have important implications for the question of the origin of biomolecular chirality. The results of preliminary NMR experiments are given, which do show evidence of a strong association between pentanucleotide RNA strands whose monomers have opposite chirality. Simple kinetic equations are solved to demonstrate the conditions under which such association can produce amplification of chirality.

Experiments on the abiotic amplification of optical activity.

Our earlier experiments are briefly reviewed, involving the abiotic generation of optical activity by exposure of DL-amino acids to various "chiral" physical forces. The enantiomeric enrichments so obtained were low, however, and additional experiments were undertaken with the objective of abiotically enhancing such small enantiomeric excesses. D not equal to L Mixtures of leucine N-carboxy anhydride gave enantiomerically enriched polymers on partial polymerization, while valine NCA mixtures behaved oppositely. Leucine polymers were also found to hydrolyze stereoselectively, providing for additional enantiomeric enhancement. A repetitive sequence of partial polymerization-hydrolysis steps is suggested as a possible mechanism for the abiotic genesis of optically enriched polypeptides on the primitive Earth.

Experiments on the amplification of optical activity.

By way of investigating possible mechanisms for the abiotic amplification of small enantiomeric excesses (e.e.'s) in almost racemic mixtures of amino acid enantiomers, we have undertaken a quantitative study of the base-initiated partial polymerization of leucine and valine N-carboxy-anhydride (NCA) enantiomer mixtures containing known excesses of both the R- and S-forms. Polymerization to the extent of ca. 50% of leucine NCA having an 8-70% e.e. of either the R- or S-enantiomer led to an e.e. enhancement in the polymer, which contained a 12-84% e.e. of that enantiomer which predominated in the original monomer NCA. A corresponding decrease in the e.e. of the initially predominant enantiomer was noted in the unpolymerized residue from each reaction. Polymerization to the extent of 25-50% of mixtures of valine NCA enantiomers containing a 12-13% e.e. of either R- or S-isomer led to polymers showing a 7-8% decrease in the e.e. of the initially predominant enantiomer, and to an increase of its e.e. in the unpolymerized residue. these divergent results, the latter of which is quite novel, are compared with earlier qualitative results in the literature and are discussed briefly from the viewpoint of both mechanism and the amplification of optical activity.