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.     

Highly enantioselective asymmetric autocatalysis of 2-alkenyl- and 2-vinyl-5-pyrimidyl alkanols with significant amplification of enantiomeric excess

2-Alkenyl- and 2-vinyl-5-pyrimidyl alkanols are highly enantioselective asymmetric autocatalysts with significant amplification of enantiomeric excess in the enantioselective addition of diisopropylzinc to 2-alkenyl- and 2-vinylpyrimidine-5-carbaldehydes. Consecutive asymmetric autocatalysis starting from 7% ee increases the ee of pyrimidyl alkanol up to 99% without the need for any other chiral auxillary.     

Fast methods of enantiopurity determination for the Soai reaction: Towards a general enantioenrichment detector?

The Soai reaction system possesses a remarkable combination of characteristics (enantioselective autocatalysis, strong positive nonlinearity leading to asymmetric amplification, ability to be triggered by wide variety of exogenous enantioenriched materials) that make it a potential starting point for a generalized detector for enantioenrichment. In this study we apply standard approaches used in pharmaceutical process research to the problem of developing a rapid method for analysis of the enantiopurity of the Soai reaction product. Several methods for rapid analysis (<1 min per sample) are described, including an approach using chiral supercritical fluid chromatography (SFC) and an approach using achiral chromatography with circular dichroism (CD) detection. Some thoughts on incorporation into a device for generalized enantioenrichment detection are presented.     

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.     

Chiral symmetry breaking: Experimental results and computer analysis of a liquid-phase autoxidation

The autoxidation of tetralin is treated as a model reaction system to define the applicability of stereospecific autocatalysis. This concept, predicting a spontaneous amplification of enantiomeric excess generated by an autocatalytic chemical reaction, is used in several theoretical models as an explanation for the origin of natural optical activity. The reaction system investigated obeys the basic criteria of these models: a chiral intermediate (tetralin hydroperoxide) is produced from an achiral substrate (tetralin) via an autocatalytic pathway where the feedback mechanism is expected to generate a state of broken chiral symmetry. In order to test the amplification capacity of this reaction a computer analysis of the kinetic scheme is performed. This simulation is derived from the known kinetic scheme of autoxidation and is validated by fitting the experimentally observed data of hydroperoxide evolution. Calculations show that this model allows powerful amplification of enantiomeric excess and a transient amplification of the optical rotation. It is also demonstrated that the model system exhibits pronounced sensitivity toward any loss of absolute configuration of the involved chiral species. Since an amplification effect results exclusively at a high degree of stereoselectivity, it is concluded that stereospecific autocatalysis is possible in systems which show template reactions, crystallization, or colloidal effects. © 1993 Wiley-Liss, Inc.     

Isotope chirality in long‐armed multifunctional organosilicon (“Cephalopod”) molecules

Long‐armed multifunctional organosilicon molecules display self‐replicating and self‐perfecting behavior in asymmetric autocatalysis (Soai reaction). Two representatives of this class were studied by statistical methods aiming at determination of probabilities of natural abundance chiral isotopomers. The results, reported here, show an astonishing richness of possibilities of the formation of chiral isotopically substituted derivatives. This feature could serve as a model for the evolution of biological chirality in prebiotic and early biotic stereochemistry.     

Demonstration of spontaneous chiral symmetry breaking in asymmetric Mannich and Aldol reactions

Spontaneous symmetry breaking in reactive systems, known as a rare physical phenomenon and for the Soai autocatalytic irreversible reaction, might in principle also occur in other, more common asymmetric reactions when the chiral product is capable to promote its formation and an element of "nonlinearity" is involved in the reaction scheme. Such phenomena are long sought after in chemistry as a possible explanation for the biological homochirality of biomolecules. We have investigated homogeneous organic stereoselective Mannich and Aldol reactions, in which the product is capable to form H-bridged complexes with the prochiral educt, and found by applying NMR spectroscopy, HPLC analysis, and optical rotation measurements 0.3-50.8% of random product enantiomeric excess under essentially achiral reaction conditions. These findings imply a hitherto overlooked mechanism for spontaneous symmetry breaking and, hence, a novel approach to the problem of absolute asymmetric synthesis and could have also potential significance for the conundrum of homochirality.     

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.     

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.     

Organocatalytic synthesis of 5-hydroxyisoxazolidine catalyzed by camphor sulfonyl hydrazines through aza-Michael addition/cyclization

A series of chiral 5-hydroxy isoxazolidines has been successfully synthesized through camphor sulfonyl hydrazine-catalyzed asymmetric aza-Michael addition reaction between N,O-protected hydroxyamines and enals. Moderate yields with moderate to good enantioselectivities (up to 96% enantiomeric excess [ee]) were achieved. It provides an alternative asymmetric approach to preparing isoxazolidine derivatives.     

An efficient system for the asymmetric acylation of (R,S)-3-n-butylphthalide catalyzed by novozyme 435

Novozyme 435 could be a highly efficient catalyst in the asymmetric acylation of (R,S)-3-n-butylphthalide in tetrahydrofuran-hexane solvents. The effect of various reaction parameters such as agitation velocity, water content, mixed media, temperature, concentration of Novozyme 435, molar ratio of acetic anhydride to (R,S)-3-n-butylphthalide, reaction time, enantiomeric excess of substrate (ee(S)), enantiomeric excess of product (ee(P)), and enantioselective ratio (E) were studied. Tetrahydrofuran markedly improved (R,S)-3-n-butylphthalide conversion, enantiomeric excess of remaining 3-n-butylphthalide, and enantiomeric ratio. The optimum media were 50% (v/v) tetrahydrofuran and 50% (v/v) hexane. Other ideal reaction conditions were an agitation velocity of 150 rpm, 0.4% (v/v) water content, temperature of 30 °C, 8 mg/mL dosage of Novozyme 435, 8:1 (0.4 mmol: 0.05 mmol) molar ratio of acetic anhydride to (R,S)-3-n-butylphthalide, and a reaction time of 48 hr. Under the optimum conditions, 96.4% ee(S) and 49.3% conversion of (R,S)-3-n-butylphthalide were achieved. In addition, enantiomeric excess of the product was above 98.0%.     

Preparation of arylzinc reagents and their use in the rhodium-catalyzed asymmetric 1,4-addition for the synthesis of 2-aryl-4-piperidones

A protocol for the catalytic asymmetric synthesis of 2-aryl-4-piperidones with high enantiomeric excess (ee) (typically > or = 99% ee) has been described here. The preparation of arylzinc reagents, which are used as nucleophiles in catalysis, is also included. The whole protocol can be completed in 10-20 h, starting from the preparation of the arylzinc reagents, depending on the reaction time of the rhodium-catalyzed process. A detailed protocol is described using the preparation of 4-fluorophenylzinc chloride and its addition to benzyl 3,4-dihydro-4-oxo-1(2H)-pyridinecarboxylate in the presence of [RhCl((R)-binap)]2 as an example.     

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.     

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.     

Asymmetric catalysis with self-organized chiral lanthanum complexes: practical and highly enantioselective epoxidation of alpha,beta-unsaturated ketones

A highly efficient and practical method for obtaining alpha,beta-epoxy ketones with high optical purities was developed. The chiral lanthanum complex self-organized in situ from lanthanum triisopropoxide, (R)-BINOL, triarylphosphine oxide, and alkyl hydroperoxide (1:1:1:1) was found to catalyze the epoxidation of alpha,beta-unsaturated ketones with tert-butyl hydroperoxide or cumene hydroperoxide at room temperature to give the corresponding epoxy ketones in high enantioselectivities (up to >99% enantiomeric excess (ee)). A remarkably high asymmetric amplification, a positive nonlinear effect, was observed in the epoxidation of chalcone, which strongly suggests the formation of a dinuclear peroxide-involved mu-complex as the active catalyst.     

Conditions for chiral asymmetry generation in the preparation of the chiral octahedral cobalt complex

We have reported that the random chiral asymmetry generation, which is a spontaneous preferential generation of one enantiomer, was observed in the synthesis of a chiral octahedral cobalt complex, cis-[CoBr(NH(3))(en)(2)]Br(2). In this article, we review our studies to explain in this system the autocatalytic growth of small enantiomeric excess that arises due to statistical fluctuations. One important experimental finding was that the rate of chiral autocatalysis increased with increasing the degree of supersaturation. Furthermore, our numerical simulation indicates that even small inhomogeneities in the reaction system may play a significant role because their effect is amplified by the autocatalytic reaction under appropriate conditions. In a small volume, fluctuations in concentration can grow if the autocatalytic growth overcomes the diffusional loss of the excess concentration from this volume. This may makes the enantiomeric excess of the chiral complex randomly fluctuate from run to run.     

Enzymatic Preparation of (R)-3-Hydroxy-2-Methylpropyl Butyrate by Asymmetric Hydrolysis

(R)-3-Hydroxy-2-methylpropyl butyrate was formed by asymmetric hydrolysis of the corresponding prochiral diester with lipase P (Amano) in high enantiomeric excess. Various physical and chemical reaction parameters were altered in order to optimize the stereoselectivity of the enzymatic reaction; low temperature (0d`C) combined with the application of salting-in salts or (polyhydric) alcohols turned out to be the most suitable systems providing the monobutyrate in 96% ee. Attempts towards chiral monobutyrate by enzymatic esterification of the corresponding prochiral diol were unsuccessful.     

Highly enantioselective bioreduction of prochiral ketones by stem and germinated plant of Brassica oleracea variety italica

Abstract

An eco-friendly and environmentally benign asymmetric reduction of a broad range of prochiral ketones employing Brassica oleracea variety italica (stems and germinated plant) as a novel biocatalyst was developed. It was found that B. oleracea variety italica could be used effectively for enantioselective bioreduction in aqueous medium with moderate to excellent chemical yield and enantiomeric excess (ee). This process is more efficient and generates less waste than conventional chemical reagents or microorganisms. Both R- and S-configurations were obtained by these asymmetric reactions. The best ee were achieved for pyridine derivatives (92–99%). The ee in germinated plant reactions were significantly higher than those of stem reactions. The low cost and the easy availability of these biocatalysts suggest their possible use for large scale preparations of important chiral alcohols.     

Discovery of new peptide-based catalysts for the direct asymmetric aldol reaction

A series of oligo-peptide based catalysts were prepared using Fmoc solid-phase peptide synthesis. It was found that peptides with N-terminal proline residues catalyzed an aldol reaction yielding enantiomeric enriched product. Peptide H-Pro-Glu-Leu-Phe-OH catalyzed the reaction with good activity and moderate enantioselectivity (66% ee). Furthermore, it was shown that an acidic side chain and/or C-termini are essential to catalysis.     

Evolution in bioids: hypercompetitivity as a source of bistability and a possible role of metal complexes as prenucleoprotic mediators of molecular asymmetry.

Spontaneous production of optically active compounds can occur through kinetic instability of an asymmetric steady state in open systems, in which two enantiomeric autocatalysts compete for a common prochiral substrate in a stereoselective reaction of order n greater than 2. For the case of n=3, a proof of instability of a symmetric reacting state in the general case, and functions of reaction parameters ('Chemical Reynolds Numbers') governing the existence and stability of 7 different steady states are derived. The 'extinct state' (without autocatalyst) is stable; a finite amount of products is required to shift it into one of the reacting steady states. A mutation from one state into another in such system ('bioids') involves an amplification of different 'kinds of information', as 'stochastic' (noise into dissipative structures), 'molecular' (autocatalysts), and 'stoichimetric' information. Stereospecific third order kinetics are believed to be realizable on octahedral metal complexes with two-dentated ligands and to have played a role in the prebiological evolution of optically active compounds.