Asymmetric autocatalysis and the origin of chiral homogeneity in organic compounds

The discovery and development of asymmetric autocatalysis, in which the structures of the chiral catalyst and the chiral product are the same, are described. Chiral 5-pyrimidyl, 3-quinolyl, and 5-carbamoyl-3-pyridyl alkanols act as highly enantioselective asymmetric autocatalysts in the enantioselective addition of diisopropylzinc to the corresponding aldehydes, such as pyrimidine-5-carbaldehyde. 2-Alkynyl-5-pyrimidyl alkanol with an enantiomeric excess (ee) of >99.5% automultiplies practically perfectly as an asymmetric autocatalyst in a yield of >99% and >99.5% ee. Asymmetric autocatalysis with an amplification of ee has thus been realized. Consecutive asymmetric autocatalysis starting with chiral 2-alkynylpyrimidyl alkanol of only 0.6% ee amplifies its ee significantly, and yields itself as the product with >99.5% ee. The reaction of pyrimidine-5-carbaldehyde and diisopropylzinc in the presence of chiral initiators with low ee's, such as secondary alcohol, amine, carboxylic acid, mono-substituted [2.2]paracyclophane, and chiral primary alcohols due to deuterium substitution, regulates the absolute configuration of the resulting pyrimidyl alkanols, and the ee of the resulting pyrimidyl alkanol is much higher than that of the chiral initiator. Leucine and [6]helicene with very low ee's, which are known to be induced by circularly polarized light (CPL), also serve as chiral initiators to produce pyrimidyl alkanol with higher ee's. Overall, the process represents the first correlation between the chirality of CPL and an organic compound with very high ee. Chiral inorganic crystals, such as quartz and sodium chlorate, act as chiral inducers in the asymmetric autocatalysis of pyrimidyl alkanol. The process correlates for the first time ever the chirality of inorganic crystals with an organic compound with very high ee.     

Amplification of chirality as a pathway to biological homochirality

Amplification of enantiomeric enrichment is a key feature for the chemical evolution of biological homochirality from the origin of chirality. The aggregations of the enantiomers by diastereomeric interactions enable the modification of their enantiomeric excess during some chemical processes. Fluorine-containing chiral compounds possess large amplification effect via distillation, sublimation and achiral chromatography by self-disproportionation. Asymmetric amplifications in enantioselective catalysis occur by the differential formation and reactivity between homochiral and heterochiral aggregate in solution.We described the amplification of ee in asymmetric autocatalysis of 5-pyrimidyl alkanol in the reaction between diisopropylzinc and pyrimidine-5-carbaldehdye. During the reactions extremely low ee (ca. 0.00005% ee) can be amplified to achieve more than 99.5% ee. Since the proposed origins of chirality such as CPL, quartz, chiral organic crystals of achiral compounds and statistical fluctuation of ee can initiate the asymmetric autocatalysis with amplification of ee, the proposed origin of chirality can be linked with enantiopure organic compound in conjunction with amplification of ee by asymmetric autocatalysis. In addition, we described that the carbon isotopically chiral compound triggers the asymmetric autocatalysis of 5-pyrimiodyl alkanol to afford the enantioenriched product with the absolute configuration correlated with that of carbon isotope chirality, that is, isotope chirality including hydrogen isotopes can control the enantioselectivity of asymmetric addition of alkyl metal reagent to aldehyde.     

Asymmetric autocatalysis of pyrimidyl alkanol and related compounds. Self-replication,amplification of chirality and implication for the origin of biological enantioenriched chirality

We discovered asymmetric autocatalysis in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, where the product 5-pyrimidyl alkanol acts as a highly efficient asymmetric autocatalyst to afford more of itself (Soai reaction). Asymmetric autocatalysis proceeded quantitatively (>99% yield), affording itself as a near enantiomerically pure (>99.5% ee) product. An extremely low enantiomeric excess (ca. 0.00005% ee) can automultiply during three rounds of consecutive asymmetric autocatalysis to >99.5% ee by asymmetric amplification. Circularly polarized light, and inorganic and organic crystals, act as the origin of chirality to trigger asymmetric autocatalysis. Asymmetric autocatalysis has enormous power to recognize and amplify the chirality of hydrogen, carbon, oxygen, and nitrogen isotopomers. Moreover, absolute asymmetric synthesis, i.e., the formation of enantioenriched compounds without the intervention of any chiral factor, is realized by asymmetric autocatalysis. By using designed molecules based on 5-pyrimidyl alkanol, the intramolecular asymmetric control, self-replication, and improvement of chiral multifunctionalized large molecules has been developed by applying asymmetric autocatalysis.     

Chiral discrimination of cryptochiral saturated quaternary and tertiary hydrocarbons by asymmetric autocatalysis

Chiral discrimination of saturated hydrocarbons has been very difficult to establish, or has not been possible at all. The first chiral discrimination of cryptochiral 5-ethyl-5-propylundecane 1, that is, (n-butyl)ethyl(n-hexyl)(n-propyl)methane, a chiral saturated quaternary hydrocarbon, which is known to exhibit practically no detectable value of optical rotation between 280 and 580 nm, has been accomplished by asymmetric autocatalysis of pyrimidyl alkanol. The absolute configuration of 1 has been determined. In the presence of (R)- or (S)-1, the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc affords (S)- and (R)-pyrimidyl alkanol with 91-97% ee, respectively. Thus, asymmetric autocatalysis serves as a powerful tool for the chiral discrimination of saturated hydrocarbons.     

Relationship between the time,yield, and enantiomeric excess of asymmetric autocatalysis of chiral 2-alkynyl-5-pyrimidyl alkanol with amplification of enantiomeric excess

Experimental and kinetic analysis of asymmetric autocatalysis with amplification of ee in the enantioselective addition of diisopropylzinc to 2-alkynylpyrimidine-5-carbaldehyde using chiral 2-alkynyl-5-pyrimidyl alkanol with low ee's are described.     

Enantioselective synthesis induced by tetrathia-[7]-helicenes in conjunction with asymmetric autocatalysis

Highly enantioenriched 5-pyrimidyl alkanol was formed using tetrathia-[7]-helicenes as a chiral initiator in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, in conjunction with asymmetric autocatalysis.     

Enantioselective synthesis induced by chiral organic-inorganic hybrid silsesquioxane in conjunction with asymmetric autocatalysis

5-Pyrimidyl alkanol with up to 96% ee was formed using chiral organic-inorganic hybrid silsesquioxane in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, in conjunction with asymmetric autocatalysis.     

Enantioselective synthesis induced by chiral crystal composed of DL-serine in conjunction with asymmetric autocatalysis

Asymmetric autocatalysis initiated by chiral crystals containing racemic DL-serine was achieved. P- and M-crystals of DL-serine acted as the source of chirality of asymmetric autocatalysis to afford highly enantioenriched (>99.5% ee) (S)- and (R)-pyrimidylalkanols after the amplification of ee. This is the first example of the usage of the crystal, which contains the same number of D- and L-enantiomers as an origin of chirality in enantioselective synthesis.     

Determination of absolute configurations of amino acids by asymmetric autocatalysis of 2-alkynylpyrimidyl alkanol as a chiral sensor

Asymmetric autocatalysis of 2-alkynyl-5-pyrimidyl alkanol is employed as a chiral sensor of 20 amino acids. Asymmetric autocatalysis using amino acids as chiral initiators gave pyrimidyl alkanols of the absolute configurations that were correlated with those of the amino acids. The enantiomeric excesses of pyrimidyl alkanol are invariably high even when the enantiomeric excess of amino acids is as low as 0.1%. Thus, by determining the absolute configuration of pyrimidyl alkanol with high enantiomeric excess, one can determine the absolute configuration of amino acids even when their enantiomeric excess is low.     

Highly enantioselective synthesis of organic compound using right- and left-handed helical silica

Highly enantiomerically enriched (up to 96-97% ee) 5-pyrimidyl alkanol was obtained by the addition of diisopropylzinc to pyrimidine-5-carbaldehyde in the presence of the artificially designed chiral inorganic material, right- and left-handed helical silica.     

Asymmetric autocatalysis induced by chiral hydrocarbon [2.2]paracyclophanes

Chiral hydrocarbon [2.2]paracyclophanes act as chiral initiators in asymmetric autocatalysis in the addition of diisopropylzinc to pyrimidine-5-carbaldehyde and give highly enantiomerically enriched 5-pyrimidyl alkanol with a reversed sense of the enantioselectivity to that of other [2.2]paracyclophanes with heteroatoms.     

Asymmetric autocatalysis: triggered by chiral isotopomer arising from oxygen isotope substitution

Trigger happy: Chiral oxygen isotopomers of hydrobenzoin ([(18) O](R)-1 and [(18) O](S)-1) acted as chiral triggers to induce the enantioselective addition of iPr(2) Zn to pyrimidine-5-carbaldehyde. An extremely small chiral influence arising from the presence of the oxygen isotope ((18) O) is amplified through asymmetric autocatalysis to enantioenrich the 5-pyrimidyl alkanol product.     

Highly Enantioselective Asymmetric Autocatalysis of Pyrimidin‐5‐yl Alkanol Induced by Chiral 1,3‐Disubstituted Hydrocarbon Allenes

1,3‐Disubstituted chiral allenes without any heteroatoms act as chiral initiators in the addition of (i‐Pr)₂Zn to pyrimidine‐5‐carbaldehyde to afford, in combination with the subsequent asymmetric autocatalysis, chiral pyrimidin‐5‐yl alkanols with up to 98% ee. The absolute configuration of the pyrimidin‐5‐yl alkanol formed depend on that of the chiral allene.     

Asymmetric synthesis of pyrimidyl alkanol without adding chiral substances by the addition of diisopropylzinc to pyrimidine-5-carbaldehyde in conjunction with asymmetric autocatalysis

Enantiomerically enriched pyrimidyl alkanol with either S or R configuration was obtained stochastically from the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc without adding chiral substances in conjunction with subsequent asymmetric autocatalysis, leading to amplification of the enantiomeric excess.     

Asymmetric autocatalysis of a ferrocene-containing chiral compound with amplification of chirality

Chiral ferrocene-containing pyrimidyl alkanol can be efficiently synthesized via asymmetric autocatalysis as an enantiomerically pure product. Moreover, a remarkable positive nonlinear effect occurs during this autocatalytic reaction. Starting from a nearly racemic seed, it is thus possible to produce a larger amount of the same compound with high ee.     

Absolute asymmetric synthesis driven by circularly polarized light

Circularly polarized light (CPL) is an inherently chiral entity and is regarded as one of the possible deterministic signals that led to the evolution of homochirality in earth. Thus, CPL as an external physical field has been widely used in a technique known as absolute asymmetric synthesis, because a product enriched in one enantiomer is formed from racemic precursor molecules without the intervention of a chiral catalyst. In this review, we retrospect the historical research of CPL-induced absolute asymmetric synthesis, including chiral organic molecules, helical polymers, supramolecular assemblies, noble metal nanostructures. However, based on these results, we concluded that the chiral photon-matter interaction is very faint due to the arrangement of molecular bonds giving rise to chiral features, is over a smaller distance than the helical pitch of CPL, leading extremely small enantiomeric excess for product. Therefore, we highlight the recently emerged technology called superchiral field, in which the superchiral far-field and near-field could enhance the dissymmetry of optical field and near-field, respectively. In sum, we hope this review could bring some enlightenment to researchers and further improve the enantioselectivity of CPL-induced absolute asymmetric synthesis.     

Synthesis of spiro diphosphines and their application in asymmetric hydrogenation of ketones

Synthesis of chiral diphosphine ligands containing a spiro scaffold was described. The ruthenium complexes of these spiro ligands were found to have extremely high activities (S/C up to 100 000) and enantioselectivities (ee up to 99.5%) in the asymmetric hydrogenation of aromatic, heteroaromatic, and alpha,beta-unsaturated ketones.     

A concise synthesis of highly enantiomerically enriched 2-alkylparaconic acid esters via ruthenium-catalyzed asymmetric hydrogenation of acylsuccinates

The catalytic asymmetric hydrogenation of acylsuccinates using RuCl₃ as a precatalyst and atropisomeric diphosphines as chiral auxiliaries allows the synthesis of optically active 2-alkylparaconic acid esters in preparative yields with enantioselectivities up to 99.5% ee.     

Preparation of chiral 3-arylpyrrolidines via the enantioselective 1,4-addition of arylboronic acids to fumaric esters catalyzed by Rh(I)/chiral diene complexes

A highly efficient rhodium-catalyzed protocol for the preparation of 2-arylsuccinic esters and 3-arylpyrrolidines of high optical purity has been achieved. In the presence of 1 mol % of a chiral diene/Rh(I) catalyst, asymmetric addition of various arylboronic acids to di-tert-butyl fumarate (3c) provides the corresponding adducts in up to 99% yield and 94→99.5% ee. Excellent enantioselectivities were also observed in the regio- and enantioselective conjugate addition of phenylboronic acid (4a) to compound 3e.     

Catalytic asymmetric ring-opening of meso-aziridines with malonates under heterodinuclear rare earth metal Schiff base catalysis

Catalytic asymmetric ring-opening of meso-aziridines with malonates is described. The combined use of two rare earth metal sources with different properties promoted the desired ring-opening reaction. A 1:1:1 mixture of a heterobimetallic La(O-iPr)(3)/Yb(OTf)(3)/Schiff base 1a (0.25-10 mol %) efficiently promoted the reaction of five-, six-, and seven-membered ring cyclic meso-aziridines as well as acyclic meso-aziridines with dimethyl, diethyl, and dibenzyl malonates, giving chiral cyclic and acyclic γ-amino esters in 99-63% yield and >99.5-97% ee.