Proline autocatalysis in the origin of biological enantioenriched chirality

Biological enantioenriched chirality is a phenomenon that in living organisms, amino acids and carbohydrates typically have the same absolute configuration. Perhaps one of the earliest attempts to delineate the origins of this phenomenon was a theory known as asymmetric autocatalysis, a reaction in which the structures of the chiral catalyst and the product are the same, and in which the chiral product acts as a chiral catalyst for its own production. In theory, this would mean that small asymmetries in the product will propagate rapidly. However, autocatalysis also relies on the cross‐inhibition of chiral states, something that would not likely be possible on primordial Earth. But recently, theories on asymmetric autocatalysis have begun to resurface as more recent findings indicate that other mechanisms exist to stabilize the homochiral states. In this study, I propose an autocatalytic cycle, and using density functional theory, prove that (1) it is plausible on primordial Earth, and (2) it propagates arbitrary asymmetries in proline. Thus, facilitating asymmetry in proline and allowing access to a wide variety of asymmetric proline‐catalyzed reactions, including those involved in the synthesis of amino acids and carbohydrates from achiral precursors.     

Enantioselective autocatalysis. IV. Implications for parity violation effects

Historically, parity violation at the contemporary biomolecular level (i.e., only L-amino acids in proteins and D-sugars in DNA and RNA) has been postulated to be the inevitable result of parity violations at the elementary particle level, involving either-decay electrons or parity violating energy differences (PVEDs)between enantiomers. These two chiral biases have in turn allegedly impressed a small but persistent chirality onto prebiotic chemistry which, after appropriate amplification, has culminated in our contemporary homochiral biopolymers. Experiments and controversies pertaining to the efficacy of these two chiral biases are reviewed briefly, with the conclusions that: a) there is no experimental evidence supporting the capability of-decay electrons or other spinpolarized chiral particles to generate chiral molecules, and b) only theoretical calculations, but no experimental evidence, support the allegation of a causal relation between PVEDs and biomolecular homochirality. We here attempt to examine the latter allegation experimentally. Spontaneous resolution under racemization conditions (SRURC) during the crystallization of the bromofluoro-1,4-benzodiazepinooxazole derivativeI is capable of affording products of high enantiomeric purity. This process, which involves very efficient stereoselective autocatalysis, has now been examined statistically. If PVED effects are operative, the SRURC of racemicI should provide, either exclusively or with a strong and consistent bias, only one enantiomer of crystallineI. However, crystallization experiments of racemicI showed no bias in its SRURC, leading to the conclusion that PVED effects are ineffective in dictating a preferred chirality in this system. Several earlier experiments in the literature leading to a similar conclusion as to the inefficacy of PVED effects in promoting a preferred chirality are noted.     

Enantioselective autocatalysis. II. Racemization studies on a 1,4-benzodiazepinooxazole derivative

Since the bromofluoro-1,4-benzodiazepinooxazole derivativeI may undergo spontaneous resolution on crystallization from methanol solution, it provides an ideal substrate on which to study the phenomenon of enantioselective autocatalysis involving spontaneous resolution under racemizing conditions (srurc). in order to augment the understanding of factors which might be important in such a process we have now undertaken to study the racemization ofI in more detail by observing its rate under a wide variety of experimental conditions.     

Enantioselective autocatalysis. III. Configurational and conformational studies on a 1,4-benzodiazepinooxazole derivative

We report here on configurational and conformational studies undertaken on the bromofluoro-1,4-benzodiazepinooxazole derivative I, which has previously been found capable of undergoing total spontaneous resolution under racemizing conditions. Due to its bridgehead N-atom I may exist in any of four diastereomeric forms,C _r N _r (orC _s N _s ) andC _r N _s (orC _s N _r ). Molecular mechanics calculations revealed that in their lowest energy conformations theC _r N _r (orC _s N _s ) diastereomers were favored over theC _r N _s (orC _s N _r ) diastereomers by some 3.42 kcal/mol, while semi-empirical quantum mechanical calculations indicated heats of formation also favoring theC _r N (orC _s N _s ) diastereomers by 3.83 kcal/mol. The¹H NMR spectra of the three crystalline modifications (, and) of I were examined in acetone, and found to be identical. These data, combined with the results of the above calculations, suggest that I exists in methanol or methanol-acetone solutions as theC _r N (orC _s N _s ) enantiomer prior to its racemization.     

Enantioselective Autocatalysis. V. The Spontaneous Resolution of Tri-o-Thymotide

We have attempted to appraise experimentally the allegation that minute chemical and physical differences due to the parity violating energy difference (PVED) between enantiomers are, after suitable autocatalytic amplification, ultimately responsible for the homochirality of contemporary biomolecules. The autocatalytic amplification technique employed involved the spontaneous resolution under racemizing conditions (SRURC) of a conglomerate during crystallization, and the system studied was the known crystallization of P(+)- or M(–)-tri-o-thymotide (TOT) as its optically active inclusion compound (clathrate) with benzene. Our premise was that if a PVED effect were operative, there should be a strong and consistent bias favoring the crystallization of one enantiomer of the TOT-benzene clathrate. Repetitive preparations of the clathrate, however, yielded crystalline products showing random optical activity. These results thus afford no evidence whatsoever for stereoselective bias due to a PVED, and are in accord with earlier statistical studies demonstrating random SRURC in other conglomerate crystallizations, again indicating the inefficacy of PVEDs to promote a preferred chirality in such systems.     

Fundamentals of chirality,resolution, and enantiopure molecule synthesis methods

The chirality of molecules is a concept that explains the interactions in nature. We may observe the same formula but different organizations revolving around the chiral center. Since Pasteur's meticulous observation of sodium ammonium tartrate crystals' structure, scientists have discovered many features of chiral molecules. The number of newly approved single enantiomeric drugs increases every year and takes place in the market. Thus, separation or resolution methods of racemic mixtures are of continued importance in the efficacy of drugs, installation of affordable production processes, and convenient synthetic chemistry practice. This article presents the asymmetric synthesis approaches and the classification of direct resolution methods of chiral molecules.     

Spontaneous absolute asymmetric synthesis in the presence of achiral silica gel in conjunction with asymmetric autocatalysis

An enantiomerically enriched pyrimidyl alkanol with either S or R configurations was obtained stochastically from the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc in the presence of achiral silica gel in conjunction with asymmetric autocatalysis with amplification of chirality.     

Spontaneous chirality conversion of [5]thiaheterohelicene in charge-transfer complexes in SDS micelles.

Racemic 2-hydroxymethylthieno[3,2-e:4,5-e']di[1]benzothiophene (5HM) with a labile helical structure was incorporated into aqueous SDS micelles containing (R)-2-(2,4,5,7-tetranitrofluoren-9-ylideneaminooxy)propionic acid (TAPA) to exhibit intense induced CD (ICD). Negative Cotton effects of the ICD gradually changed to reversed Cotton effects with time or sonication. This phenomenon of chirality conversion was attributable to conformational alterations of 5HM from an (M) helix to a (P), accompanied by compositional alterations of 5HM-(R)-TAPA charge-transfer (CT) complexes from 1/2 to 1/1. The conversion rate from the (M) enantiomer to the (P) was obtained from the change of the ICD intensities with time and the chiral discrimination energy exerted in the 1:1 CT complex was estimated from the temperature dependence of the ICD intensities.     

Mechanism of chiral asymmetry generation by chiral autocatalysis in the preparation of chiral octahedral cobalt complex

Chiral asymmetry generation, the predominant production of one enantiomer in a non-chiral environment, could occur in the production of the chiral complex cis-[CoBr(NH₃)(en)₂]Br₂ by the reaction of [Co(H₂O)₂{(OH)₂Co(en)₂}₂](SO₄)₂ with ammonium bromide in an aqueous medium. The main kinetic steps in the reaction system have been determined. During the reaction, the product crystallizes at an early stage. When a very small amount of crystalline enantiomer was added to the reaction system at an early stage, the same enantiomer was produced preferentially; in addition, the enantiomeric excess of the product increased with increasing the stirring rate. Thus, it seems that each enantiomer generates chiral crystals that could self-replicate through secondary nucleation when the solution is stirred; these crystals in turn enhance the production of the same enantiomer. With a computer code that simulates such a kinetic mechanism, it is shown that enantiomeric excess observed in the experiments could be reproduced. Chirality 10:343–348, 1998. © 1998 Wiley-Liss, Inc.     

Spontaneous generation of adriamycin semiquinone radicals at physiologic pH.

Adriamycin semiquinone radicals are spontaneously generated by adriamycin solutions at physiologic pH. Rate of radical formation and equilibrium-state radical yield increase with increasing pH from 7.4 to 8.85. The radicals are oxygen sensitive, but the mechanism of radical formation is oxygen independent and associated with proton removal from the dihydroquinone of adriamycin. The less cardiotoxic and non-mutagenic (Ames test) anthracycline 5-iminodaunorubicin does not form semiquinone radicals spontaneously at physiologic pH.     

A model for the prebiotic synthesis of peptides which throws light on the origin of the genetic code and the observed chirality of life

A model is proposed which indicates that peptides could have been synthesized on RNA templates. L-amino acids are selectively trapped and orientated in clefts in an apparently stable RNA structure attached to a solid phase. Each cleft is bounded by three bases which correspond to the codon for that amino acid. Rotation during a dehydration phase orientates the amino acids so that peptide bond formation can occur by condensation. Rehydration releases the formed peptides.     

Life and chirality beyond the earth.

An attempt is made to show that the phenomenon of chirality- of which optical activity is but one consequence- is by no means restricted to life on Earth, but is common throughout the universe. Several independent sources have been investigated including: statistical fluctuations; stereoselective physical factors; and energetic differences between enantiomeric molecules. It is emphasised that a search for chirality as an indicator for life elsewhere in space provides an excellent tool for the fascinating question of exobiology. Still one must be aware of the limitations of the experimental methods and their interpretations.     

Spontaneous generation of selectable variation in the brain

Selection models of behavior presuppose selectable variation, diversity in the brain that is stable over time. Diversity can arise spontaneously through the mutual interactions of cell assemblies, which are postulated to align or disalign their neighbors into processing modes conforming to or opposite from their own. These processes are similar to magnetization and crystallization. If aligning and disaligning influences are distributed at random, a state resembling a spin glass can arise, where processing modes are highly varied in space but stable in time. If disalignment occurs regularly at the points of a two-dimensional lattice, and elsewhere the interactions are aligning, a pattern emerges with properties remarkably similar to visual orientation columns. These patterns are maintained dynamically, and emerge statistically without detailed genetic specification.Special issue dedicated to Dr. Eugene Roberts.     

Freezing effect on chirality generation of DL-alanine-N-carboxy-anhydride oligomerization in aqueous solution

This article is concerned with a study of the role of ice in the synthesis of oligopeptides containing L- or D-enantiomeric excess (ee) from racemic alanine. With this aim, the oligomerization of DL-alanine-N-carboxyanhydride was investigated by keeping this activated derivative in liquid (+22 degrees C) or frozen (-20 degrees C) aqueous solutions for 30 days. The aqueous solution of the peptide mixtures were gel-filtered and the aliquots of the fractions were completely hydrolyzed to alanine monomers. These monomers were then derivatized with 1-fluoro-2,4-dinitrophenyl-5-L-alanine amide (Marfey's reagent) and analyzed by RP-HPLC to reveal the occasional enantiomeric excess of L- or D-Ala. The mass spectrometry of the gel-filtered fractions pointed to open-chain peptide mixtures together with a slight amount of cyclic ones, where the residue numbers ranged between 5-8. Our studies indicated that an enantiomeric excess of L- or D-Ala appeared in some oligopeptide fractions. Their excesses were significantly larger in the frozen than liquid solution. Speculations are made as concerns the implications of our findings in the events of prebiotic chemistry.     

In vitro study on gas generation and prebiotic effects of some carbohydrates and their mixtures

This study was carried out to examine the effect of inulin (IN), fructooligosaccharide (FOS), polydextrose (POL) and isomaltooligosaccharides (ISO), alone and in combination, on gas production, gas composition and prebiotic effects. Static batch culture fermentation was performed with faecal samples from three healthy volunteers to study the volume and composition of gas generated and changes in bacterial populations. Four carbohydrates alone or mixed with one another (50:50) were examined. Prebiotic index (PI) was calculated and used to compare the prebiotic effect. The high amount of gas produced by IN was reduced by mixing it with FOS. No reduction in gas generation was observed when POL and ISO mixed with other substrates. It was found that the mixture of IN and FOS was effective in reducing the amount of gas produced while augmenting or maintaining their potential to support the growth of bifidobacteria in faecal batch culture as the highest PI was achieved with FOS alone and a mixture of FOS and IN. It was also found that high volume of gas was generated in presence of POL and ISO and they had lower prebiotic effect. The results of this study imply that a mixture of prebiotics could prove effective in reducing the amount of gas generated by the gut microflora.