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.     

Enantioselective synthesis of near enantiopure compound by asymmetric autocatalysis triggered by asymmetric photolysis with circularly polarized light

Right- and left-handed circularly polarized light (CPL) has been proposed as one of the origins of homochirality of biomolecules. However, the enantiomeric excess induced by CPL has been only very low (<2% ee). We found the unprecedented example of asymmetric autocatalysis triggered directly by a chiral physical factor, that is, right- and left-handed CPL, leading to a near enantiopure compound. Asymmetric photolysis of racemic pyrimidyl alkanol by r-CPL irradiation followed by asymmetric autocatalysis affords (R)-pyrimidyl alkanol with >99.5% ee. On the other hand, irradiation with l-CPL affords (S)-pyrimidyl alkanol with >99.5% ee. Thus, chiral physical power, such as CPL, in conjunction with asymmetric autocatalysis, provides a highly enantioenriched compound.     

Chiral secondary alcohol-induced asymmetric autocatalysis: correlation between the absolute configuration of the chiral initiators and the product

In the presence of various chiral secondary alcohols as chiral initiators, an enantioselective alkylation of a pyrimidine-5-carbaldehyde using diisopropylzinc was examined: a pyrimidyl alkanol was obtained in high yield and enantiomeric excess. The correlation between the absolute configuration of the chiral secondary alcohols and the pyrimidyl alkanol is discussed.     

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 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.     

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.     

Enantioselective synthesis utilizing enantiomorphous organic crystal of achiral benzils as a source of chirality in asymmetric autocatalysis

Chiral crystals of achiral benzils act as efficient chiral initiators of asymmetric autocatalysis to afford highly enantioenriched pyrimidyl alkanols whose absolute configurations depend upon the enantiomorph of the crystal used in conjunction with asymmetric autocatalysis with amplification of enantiomeric excess.     

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.     

Crystal Structure of the Isopropylzinc Alkoxide of Pyrimidyl Alkanol: Mechanistic Insights for Asymmetric Autocatalysis with Amplification of Enantiomeric Excess

Asymmetric amplification during self‐replication is a key feature that is used to explain the origin of homochirality. Asymmetric autocatalysis of pyrimidyl alkanol in the asymmetric addition of diisopropylzinc to pyrimidine‐5‐carbaldehyde is a unique example of this phenomenon. Crystallization of zinc alkoxides of this 5‐pyrimidyl alkanol and single‐crystal X‐ray diffraction analysis of the alkoxide crystals reveal the existence of tetramer or higher oligomer structures in this asymmetric autocatalytic system.     

Chiral imines prepared from 1-(2-aminoalkyl)aziridines as novel chiral shifts reagents for efficient recognition of acids

Optically pure, chiral imines synthesized from the corresponding aldehydes and 1-(2-aminoalkyl)aziridines in good chemical yields, have been assessed as an NMR chiral shift reagents for effective discrimination of the signals of some acids (mandelic acid and its derivatives and N-protected amino acid). The title compounds have proven to be very useful for the determination of enantiomeric purity and absolute configuration of the aforementioned acid derivatives.     

Achiral Inorganic Gypsum Acts as an Origin of Chirality through Its Enantiotopic Surface in Conjunction with Asymmetric Autocatalysis

Achiral inorganic gypsum (CaSO₄⋅2 H₂O) triggers the asymmetric autocatalysis of pyrimidyl alkanol on its two‐dimensional enantiotopic faces to give highly enantioenriched alkanol products with absolute configurations corresponding to the respective enantiotopic surfaces. This is the first example of highly enantioselective synthesis on the enantiotopic surface of an achiral mineral.     

Enantioselective radical-mediated allylation of α-iododihydrocoumarins using Lewis acids generated from chiral sulfonamides

Enantioseletive radical-mediated allylation using chiral Lewis acids generated from sulfonamides is described. Asymmetric allylation took place in 54% enantiomeric excess to form a chiral quaternary carbon center with R configuration. The present reaction proceeded equally well with a substoichiometric amount of a chiral Lewis acid as with a stoichiometric amount.     

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.     

Synthesis of new chiral fluorescent sensors and their applications in enantioselective discrimination

New chiral fluorescent sensors derived from tetraphenylethylene and proline hydrazide were synthesized and applied in the chiral recognition of various chiral compounds, including unprotected amino acids, acidic compounds, chiral amines and even neutral alcohols. These results demonstrated that the excellent enantioselective response ability to various chiral substrates could be attributed to the –NH moieties of pyrrolidine ring and thiourea unit which acted as hydrogen-bonding donors. This result is of potential significance in enantiomeric discrimination and high-throughput analysis of the enantiomeric purity of chiral guests.     

不对称自催化反应

不对称自催化反应是指由不对称反应生成的手性产物自身作为催化剂的反应过程。不对称自催化具有手性自动放大、反应活性较高、产物处理较易、反应体系连续等特点,是不对称化学的一个新的领域。不对称自催化反应结合手性放大作用,使人们对手性起源有了新的认识。自1990年代以来该方面的探索和研究取得令人注目的重大突破。本文综述了近年来不对称自催化反应的新进展。     

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.     

Enantioselective CD analysis of amino acids based on chiral amplification with a stereodynamic probe

The condensation between stereolabile 1,8-bis(3′-formyl-4′-hydroxyphenyl)naphthalene, 1, and two amino acid molecules results in the formation of chiral diimines exhibiting strong CD signals. This reaction has been used to develop a chiroptical sensing method for the determination of the absolute configuration and enantiomeric composition of unprotected amino acids. This sensing approach is based on distinctive chiral amplification due to central-to-axial chirality induction within the diimine scaffold formed and does not require the use of an enantiopure ligand or metal complex.     

In Situ Mass Spectrometric and Kinetic Investigations of Soai's Asymmetric Autocatalysis

Chemical reactions that lead to a spontaneous symmetry breaking or amplification of the enantiomeric excess are of fundamental interest in explaining the formation of a homochiral world. An outstanding example is Soai's asymmetric autocatalysis, in which small enantiomeric excesses of the added product alcohol are amplified in the reaction of diisopropylzinc and pyrimidine-5-carbaldehydes. The exact mechanism is still in dispute due to complex reaction equilibria and elusive intermediates. In situ high-resolution mass spectrometric measurements, detailed kinetic analyses and doping with in situ reacting reaction mixtures show the transient formation of hemiacetal complexes, which can establish an autocatalytic cycle. We propose a mechanism that explains the autocatalytic amplification involving these hemiacetal complexes. Comprehensive kinetic experiments and modelling of the hemiacetal formation and the Soai reaction allow the precise prediction of the reaction progress, the enantiomeric excess as well as the enantiomeric excess dependent time shift in the induction period. Experimental structural data give insights into the privileged properties of the pyrimidyl units and the formation of diastereomeric structures leading to an efficient amplification of even minimal enantiomeric excesses, respectively.     

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.