Asymmetric autocatalysis and its application to chiral discrimination

Chiral pyrimidyl, quinolyl, and pyridyl alkanols act as asymmetric autocatalysts with significant amplification of enantiomeric excess (ee) in the enantioselective addition of diisopropylzinc to pyrimidine-5-, quinoline-3-, and pyridine-3-carbaldehydes, respectively. 2-Alkynyl-5-pyrimidyl alkanol with as low as 0.6% ee automultiplies during the consecutive asymmetric autocatalysis with increasing ee to as high as >99.5%. Asymmetric autocatalysis is applied to chiral discrimination of organic compounds. In the presence of methyl mandelate or 2-butanol with very low ee's (0.05-0.1%) as chiral initiators, the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc affords pyrimidyl alkanol with higher ee's with the correlated absolute configurations to those of the chiral initiators. Chirality of amino acids (such as leucine) and helicenes with very low ee's are also discriminated by asymmetric autocatalysis, affording pyrimidyl alkanol with very high ee's. Asymmetric autocatalysis also discriminates the chirality of primary alcohols-alpha-d, monosubstituted [2.2]paracyclophanes and octahedral cobalt complex with achiral ligands of which the chirality is due to the topology of coordination of the achiral ligand. Even the chirality of inorganic crystals such as quartz and sodium chlorate is discriminated by asymmetric autocatalysis of pyrimidyl alkanol. Thus, asymmetric autocatalysis provides a unique method for the discrimination of chiral compounds and crystals.     

d-Amino acids in molecular evolution in space – Absolute asymmetric photolysis and synthesis of amino acids by circularly polarized light

Living organisms on the Earth almost exclusively use l-amino acids for the molecular architecture of proteins. The biological occurrence of d-amino acids is rare, although their functions in various organisms are being gradually understood. A possible explanation for the origin of biomolecular homochirality is the delivery of enantioenriched molecules via extraterrestrial bodies, such as asteroids and comets on early Earth. For the asymmetric formation of amino acids and their precursor molecules in interstellar environments, the interaction with circularly polarized photons is considered to have played a potential role in causing chiral asymmetry. In this review, we summarize recent progress in the investigation of chirality transfer from chiral photons to amino acids involving the two major processes of asymmetric photolysis and asymmetric synthesis. We will discuss analytical data on cometary and meteoritic amino acids and their potential impact delivery to the early Earth. The ongoing and future ambitious space missions, Hayabusa2, OSIRIS-REx, ExoMars 2020, and MMX, are scheduled to provide new insights into the chirality of extraterrestrial organic molecules and their potential relation to the terrestrial homochirality. This article is part of a Special Issue entitled: d-Amino acids: biology in the mirror, edited by Dr. Loredano Pollegioni, Dr. Jean-Pierre Mothet and Dr. Molla Gianluca.     

On the asymmetric autocatalysis of aldol reactions: The case of 4‐nitrobenzaldehyde and acetone. A critical appraisal with a focus on theory

Under neutral conditions, spontaneous mirror symmetry breaking has been occasionally reported for aldol reactions starting from achiral reagents and conditions. Chiral induction might be interpreted in terms of autocatalysis exerted by chiral mono‐aldol or bis‐aldol products as source of initial enantiomeric excesses, which may account for such experimental observations. We describe here a thorough Density Functional Theory (DFT) study on this complex and otherwise difficult problem, which provides some insights into this phenomenon. The picture adds further rationale to an in‐depth analysis by Moyano et al, who showed the isolation and characterization of bis‐aldol adducts and their participation in a complex network of reversible steps. However, the lack of enantiodiscrimination (ees vanish rapidly in solution) suggests, according to the present results, a weak association in complexes formed by the catalysts and substrates. The latter would also be consistent with almost flat transition states having similar heights for competitive catalyst‐bound transition structures (actually, we were unable to locate them at the level explored). Overall, neither autocatalysis as once conjectured nor mutual inhibition of enantiomers appears to be operating mechanisms. Asymmetric amplification in early stages harnessing unavoidable enantiomeric imbalances in reaction mixtures of chiral products represents a plausible interpretation.     

Racemization and the origin of optically active organic compounds in living organisms

The organic compounds synthesized in prebiotic experiments are racemic mixtures. A number of proposals have been offered to explain how asymmetric organic compounds formed on the Earth before life arose, with the influence of chiral weak nuclear interactions being the most frequent proposal. This and other proposed asymmetric syntheses give only slight enantiomeric excess and any slight excess will be degraded by racemization. This applies particularly to amino acids where half-lives of 10(5)-10(6) years are to be expected at temperatures characteristic of the Earth's surface. Since the generation of chiral molecules could not have been a significant process under geological conditions, the origins of this asymmetry must have occurred at the time of the origin of life or shortly thereafter. It is possible that the compounds in the first living organisms were prochiral rather than chiral; this is unlikely for amino acids, but it is possible for the monomers of RNA-like molecules.     

Spontaneous Mirror Symmetry Breaking in the Aldol Reaction and its Potential Relevance in Prebiotic Chemistry

The origin of the single chirality of most biomolecules is still a great puzzle. Carbohydrates could form in the formose reaction, which is proposed to be autocatalytic and contains aldol reaction steps. Based on our earlier observation of organoautocatalysis and spontaneous enantioenrichment in absence of deliberate chiral influences in the aldol reaction of acetone and p-nitrobenzaldehyde we suggest that a similar effect might be present also in the aldol reactions involved in gluconeogenesis. Herein we show that reactant precipitation observed in our earlier reported experiments does not affect the asymmetric autocatalysis in the aldol reaction we studied. We explain the phenomenon of spontaneous mirror symmetry breaking in such organocatalytic homogenous systems qualitatively by non-linear reaction network kinetics and classical transition state theory.     

Analysis of the mechanism of asymmetric amplification by chiral auxiliary trans-1,2-diaminocyclohexane bistriflamide

Asymmetric amplification is a phenomenon in which the enantiomeric excess (ee) of a product is higher than that of a chiral auxiliary for a catalyst. We analyzed the mechanism of asymmetric amplification observed in the addition of diethylzinc (Et(2)Zn) to benzaldehyde (PhCHO) to synthesize 1-phenyl-1-propanol in the presence of trans-1,2-diaminocyclohexane bistriflamide (DCBF) and titanium tetraisopropoxide (TIOP). In a manner similar to the reaction in which 1-piperidino-3,3-dimethyl-2-butanol is a chiral auxiliary for the catalyst, when asymmetric amplification was observed, the ee of the product varied as the reaction progressed. The mechanisms of variation in ee in the two reactions, however, were different. No asymmetric amplification was observed when TIOP and PhCHO were added to a mixture of DCBF and Et(2)Zn, while the ee of the product was always higher than that of DCBF when PhCHO and Et(2)Zn were added to a mixture of DCBF and TIOP. In the latter case, the product ee decreased as the reaction progressed. The results indicate that DCBF forms inactive heterochiral complex causing an increase in the ee of DCBF in the solution, which is the chiral auxiliary for the catalyst. But the complex is not very stable and gradually dissociates due to the reaction with Et(2)Zn. As a result, the asymmetric amplification decreases as the reaction progresses.     

Use of chiral auxiliaries in the asymmetric synthesis of biologically active compounds: A review

This review article describes the use of some of the most popular chiral auxiliaries in the asymmetric synthesis of biologically active compounds. Chiral auxiliaries derived from naturally occurring compounds, such as amino acids, carbohydrates, and terpenes, are considered essential tools for the construction of highly complex molecules. We highlight the auxiliaries of Evans, Corey, Yamada, Enders, Oppolzer, and Kunz, which led to remarkable progress in asymmetric synthesis in the last decades and continue to bring advances until the present day.     

'Five at one stroke': proline and small peptides in the stereoselective de novo synthesis and enantiotopic functionalization of carbohydrates

Asymmetric catalysis with the simple amino acid proline (so called 'enamine catalysis') arrested big attention in the last few years since the re-discovery of the Hajos-Parrish-Eder-Sauer-Wiechert reaction. After basic mechanistic studies, probing scope and limitations of the catalyst and the corresponding reactions, this concept has now emerged to a state where it is applied to the assembly of up to five stereogenic centers of carbohydrates, not really 'at one stroke', but in only two simple synthetic operations. Beyond, it is not only possible to build up complicated natural products elegantly, but also to address selectively the similar functional groups of carbohydrates by small peptidic catalysts. This short review covers the recent developments of organocatalysis in both fields, with special emphasis on the asymmetric assembly and selective derivatization of carbohydrates.     

Asymmetric Autocatalysis Induced by Chiral Crystals of Achiral Tetraphenylethylenes

The achiral hydrocarbon tetraphenylethylene crystallizes in enantiomorphous forms (chiral space group: P2₁) to afford right- and left-handed hemihedral crystals, which can be recognized by solid-state circular dichroism spectroscopic analysis. Chiral organic crystals of tetraphenylethylene mediated enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde to give, in conjunction with asymmetric autocatalysis with amplification of chirality, almost enantiomerically pure (S)- and (R)-5-pyrimidyl alkanols whose absolute configurations were controlled efficiently by the crystalline chirality of the tetraphenylethylene substrate. Tetrakis(p-chlorophenyl)ethylene and tetrakis(p-bromophenyl)ethylene also show chirality in the crystalline state, which can also act as a chiral substrate and induce enantioselectivity of diisopropylzinc addition to pyrimidine-5-carbaldehyde in asymmetric autocatalysis to give enantiomerically enriched 5-pyrimidyl alkanols with the absolute configuration correlated with that of the chiral crystals. Highly enantioselective synthesis has been achieved using chiral crystals composed of achiral hydrocarbons, tetraphenylethylenes, as chiral inducers. This chemical system enables significant amplification of the amount of chirality using spontaneously formed chiral crystals of achiral organic compounds as the seed for the chirality of asymmetric autocatalysis.     

Glycine and alanine synthesis from formaldehyde and hydroxylamine in the field of ultrasound waves

High intensity ultrasound waves coupled with other form of energy obviously were initiators of pre-biochemical reactions; these reactions occurred in the water masses of the primordial Earth.Essential biological substances like formaldehyde, ammonia, hydrocyanic acid, and amino acids compounds similar to carbohydrates by their properties were synthesized in the field of ultrasound waves in model experiments.The main partners of these reactions are water and gases of reductional atmosphere: hydrogen, carbon monoxide, methane, nitrogen and argon.Formation of amino acids takes place in aqueous solutions of formaldehyde and hydroxylamine. The sonication yielded alanine and glycine, 2.0×10^–7 and 1.8×10^–7 molecules per 100 eV respectively.     

基于噁唑烷酮的不对称催化合成构建多官能化手性氨基酸类化合物

多官能化手性氨基酸及其衍生物是一类重要的手性药物以及合成手性药的关键中间体,如现在大量用于临床的左甲状腺素、赖诺普利、阿莫西林、缬沙坦、头孢氨苄以及青霉素等。进行多官能化手性氨基酸类化合物的不对称催化合成,可为新型化学药的设计与发现开辟新的视野。噁唑烷酮(Azlactone)被证明是合成四取代氨基酸衍生物的优秀底物。可通过不对称催化手段向其中引入需要的基团,再经多取代的噁唑烷酮直接开环得到一系列的目标化合物。本文主要综述了近年来基于恶唑烷酮的不对称催化反应构建四取代氨基酸类化合物的研究。     

Chiral symmetry conservation principle

We show a chiral symmetry conservation principle based on chemical kinetics using stochastic results. Suppose the chiral symmetry conservation is evoked, and our universe can be considered globally asymmetric. In that case, there are at least two mirrored asymmetric universes if all the chiral properties are strongly correlated. However, if the chiral correlations are weak or nonexistent, there are possibly Many-(Chiral-Symmetry)-Worlds. Alternatively, if our universe is only locally asymmetric, there could be a single universe with segregated chiral regions. The possible mechanisms of the primordial chiral symmetry breaking can only be found if the chiral symmetry is not truly conserved by assuming the initial racemic conditions. In that case, our universe is asymmetric and could be alone. On the other hand, if the chiral symmetry is conserved, there is no chance of finding the primordial chiral symmetry breaking. Based on this conservation (or not), it is possible to infer two opposite hypotheses, where two general scenarios about the chiral universes are possible.     

Induction and repression of the collagenase synthesis in Acinetobacter sp.]

The synthesis of collagenase in Acinetobacter sp. was found to be inducible by denatured collagen and by its high molecular weight fragments. The presence in the inducer of part of the tertiary structure appear to be indispensable. On the other hand, an addition of Casamino acids, meat protein hydrolysate, or a mixture of amino acids with a similar composition to gelatin does not stimulate collagenase synthesis. Enzyme production was severely repressed in the early phase of growth by glucose, arabinose, and ribose, single amino acids, proline, hydroxyproline, alanine, glutamic acid or casein acid hydrolysate. A mechanism of repression similar to catabolite repression was involved in the phenomenon caused by carbohydrates. However, the fact that cyclic adenosine 3'5-monophosphate did not overcome the repression caused by amino acids or Casamino acids, in contrast to classical catabolite repression, suggests that these two forms of repression may be distinct.     

5-(pyrrolidin-2-yl)-1H-tetrazole and 5-[(pyrrolidin-2-yl)methyl]-1H-tetrazole: proline surrogates with increased potential in asymmetric catalysis

Catalytic enantioselective methodology has dramatically been enriched by the re-discovery of the simple amino acid proline as a chiral catalyst in the year 2000. Although no catalyst offers such a simple and broad access to quite complex reaction products, as does proline, its synthetic potential is not unrestricted, what is especially connected to its poor solubility in organic media. Exchange of the carboxylic moiety by a tetrazole unit leads to proline surrogates, that by far outperform proline with respect to yield, enantioselectivity, reaction time, substrate and solvent scope, catalyst loading, and stoichiometry of the compounds used in excess. These factors are discussed and critically compared with selected representative proline-catalyzed reactions.     

Solid-state vibrational circular dichroism studies on the conformation of an amino acid molecule in crystalline state

The present article reviews the results of solid-state vibrational circular dichroism (SD-VCD) measurements on the crystals of amino acids. The investigated series were Ala, Ile, Leu, Phe, Ser, Val, and Thr. Spectra were recorded for the samples containing both D- and L-enantiomers. The molecular conformation in a crystalline state was compared among the series. Molecule optimization of their conformation under intermolecular interactions in crystalline states was revealed. One noteworthy aspect was that some VCD peaks were remarkably enhanced in comparison with the solution states. This fact was rationalized in terms of vibrationally coupled delocalization in a closely stacked pair. In addition, for a molecule with two asymmetric carbons, the signs of the VCD peaks were determined by the interplay between the two chiral centers. Lastly, the roles of the theoretical approach based on density functional theory calculations were described.     

Photochemical Concepts on the Origin of Biomolecular Asymmetry

Biopolymers like DNA and proteins are strongly selective towards the chirality of their monomer units. The use of homochiral monomers is regarded as essential for the construction and function of biopolymers; the emergence of the molecular asymmetry is therefore considered as a fundamental step in Chemical Evolution. This work focuses on physicochemical mechanisms for the origin of biomolecular asymmetry. Very recently two groups, one from Allamandola at NASA Ames and the other from our Inter-European team, demonstrated simultaneously the spontaneous photoformation of a variety of chiral amino acid structures under simulated interstellar conditions. Since both groups used unpolarized light for the photoreaction the obtained amino acids turned out racemic as expected. The obtained experimental data support the assumption that tiny ice grains can furthermore play host to important asymmetric reactions when irradiated by interstellar circularly polarized ultraviolet light. It is possible that such ice grains could have become incorporated into the early cloud that formed our Solar System and ended up on Earth, assisting life to start. Several lines of evidence suggest that some of the building blocks of life were delivered to the primitive Earth via (micro-) meteoroids and/or comets. These results suggest that asymmetric interstellar photochemistry may have played a significant part in supplying Earth with some of the enantioenriched organic materials needed to trigger life. The search for the origin of biomolecular homochirality leads to a strong interest in the fields of asymmetric photochemistry with special emphasis on absolute asymmetric synthesis. We outline here the theoretical background on asymmetric interstellar ice photochemistry, summarize recent concepts and advances in the field, and discuss briefly its implications. The obtained data are crucial for the design of the enantioselective COSAC GC-MS experiment onboard the ROSETTA spacecraft to a comet to be launched in the very near future.     

Comet impacts and chemical evolution on the bombarded Earth

Amino acids yields for previously published shock tube experiments are used with minimum Cretaceous-Tertiary (K/T) impactor mass and comet composition to predict AIB amino acid K/T boundary sediment column density. The inferred initial concentration of all amino acids in the K/T sea and in similar primordial seas just after 10 km comet impacts would have been at least 10^–7 M. However, sinks for amino acids must also be considered in calculating amino acid concentrations after comet impacts and in assessing the contribution of comets to the origin of life. The changing concentration of cometary amino acids due to ultraviolet light is compared with the equilibrium concentration of amino acids produced in the sea from corona discharge in the atmosphere, deposition in water, and degradation by ultraviolet light. Comets could have been more important than endogenous agents for initial evolution of amino acids. Sites favorable for chemical evolution of amino acids are examined and it is concluded that chemical evolution could have occurred at or above the surface even during periods of intense bombardment of Earth before 3.8 billion years ago.     

Chirality and life

The crucial role of homochirality and chiral homogeneity in the self-replication of contemporary biopolymers is emphasized, and the experimentally demonstrated advantages of these chirality attributes in simpler polymeric systems are summarized. The implausibility of life without chirality and hence of a biogenic scenario for the origin of chiral molecules is stressed, and chance and determinate abiotic mechanisms for the origin of chirality are reviewed briefly in the context of their potential viability on the primitive Earth. It is concluded that all such mechanisms would be non-viable, and that the turbulent prebiotic environment would require an ongoing extraterrestrial source for the accumulation of chiral molecules on the primitive Earth. A scenario is described wherein the circularly polarized ultraviolet synchrotron radiation from the neutron star remnants of supernovae engenders asymmetric photolysis of the racemic constituents in the organic mantles on interstellar dust grains, whereupon these chiral constituents are transported repetitively to the primative Earth by direct accretion of the interstellar dust or through impacts of comets and asteroids.     

First Results of the RAMBAS Experiment on Investigation of the Radiation Mechanism of Chiral Influence

The first results of the RAdiation Mechanism of Biomolecular ASymmetry (RAMBAS) experiment on investigation of the radiation mechanism of the influence on chiral molecules, as a factor leading to origination of chiral asymmetry are presented. It was found that irradiation of simple achiral materials by a flux of electrons from radioactive source initiated the synthesis of amino acids, and it resulted in asymmetric degradation and chiral asymmetry in a racemic mixture of amino acids. The results obtained can be important for the solution of the origin-of-life and biological homochirality problems.