Tsuneomi Kawasaki

Asymmetric autocatalysis triggered by carbon isotope (13C/12C) chirality.

The origin of chirality in asymmetric autocatalysis is due to carbon isotope substitution. Resolving Isotopically Chiral Alcohols Autocatalytic reactions, which are accelerated by their own product, can amplify small imbalances in the chiral distribution of starting materials. A particularly effective system is the alkylation of certain aldehydes by diisopropyl zinc, which becomes increasingly stereoselective as the chiral alkoxide product coordinates to unreacted zinc centers. Kawasaki et al. (p. 492, published online 26 March) show that the sense of enantioselection in this system can be influenced by a factor as subtle as chirality in an alcohol that arises only because two positions differ in having 12C and 13C atoms. Isotopically chiral ligands were carefully prepared by using methods that would avoid chiral contaminants, and each led to a distinct enantiomer with enantiomeric excesses exceeding 90%. Many apparently achiral organic molecules on Earth may be chiral because of random substitution of the 1.11% naturally abundant 13C for 12C in an enantiotopic moiety within the structure. However, chirality from this source is experimentally difficult to discern because of the very small difference between 13C and 12C. We have demonstrated that this small difference can be amplified to an easily seen experimental outcome using asymmetric autocatalysis. In the reaction between pyrimidine-5-carbaldehyde and diisopropylzinc, addition of chiral molecules in large enantiomeric excess that are, however, chiral only by virtue of isotope substitution causes a slight enantiomeric excess in the zinc alkoxide of the produced pyrimidyl alkanol. Asymmetric autocatalysis then leads to pyrimidyl alcohol with a large enantiomeric excess. The sense of enantiomeric excess of the product alcohol varies consistently with the sense of the excess enantiomer of the carbon isotopically chiral compound.

Asymmetric Autocatalysis with Amplification of Chirality

We found that chiral 5-pyrimidyl alkanols are highly enantioselective asymmetric autocatalysts forthe addition of i-Pr2Zn to the corresponding aldehyde.Asymmetric autocatalysis with amplification of ee from extremely low (0.00005%) ee to >99.5% ee wasrealized for the first time by consecutive asymmetric autocatalysis. The chirality of CPL was directlycorrelated with the chirality of the pyrimidyl alkanol with high ee by asymmetric photodegradation of theracemic pyrimidyl alkanol in combination with asymmetric autocatalysis. Chiral inorganic crystals suchas quartz act as chiral triggers and regulate the sense of the asymmetric autocatalysis. Chiral organiccrystals composed of an achiral compound such as hippuric acid act as the initial source of chirality forasymmetric autocatalysis to produce the nearly enantiomerically pure product. Highly sensitive chiral discriminationof amino acids with low ee is described. Direct examination of extraterrestrial chirality was performedon meteorites by applying asymmetric autocatalysis as the chiral sensor. Spontaneous absolute asymmetricsynthesis is described in the formation of enantiomerically enriched pyrimidyl alkanol from the reactionof pyrimidine-5-carbaldehyde and i-Pr2Zn withoutadding any chiral substance in combination with asymmetric autocatalysis. Asymmetric autocatalysis of a chiralpyrimidyl alkanol is the only possible method to discriminate a cryptochiral quaternary saturated hydrocarbon,whose chirality is not capable of determination by any current method. The discrimination of chiralitydue to deuterium substitution is also accessible by the highly sensitive asymmetric autocatalysis.

Asymmetric Autocatalysis of Pyrimidyl Alkanol and Its Application to the Study on the Origin of Homochirality

CONSPECTUS: Amplification of enantiomeric excess (ee) is a key feature for the chemical evolution of biological homochirality from the origin of chirality. We describe the amplification of ee in the asymmetric autocatalysis of 5-pyrimidyl alkanols in the reaction between diisopropylzinc (i-Pr2Zn) and pyrimidine-5-carbaldehydes. During the reaction, an extremely low ee (ca. 0.00005% ee) can be amplified to >99.5% ee, and therefore, the initial slightly major enantiomer is automultiplied by a factor of ca. 630000, while the initial slightly minor enantiomer is automultiplied by a factor of less than 1000. In addition, pyrimidyl alkanols with various substituents at the 2-position of the pyrimidine ring, 3-quinolyl alkanol, 5-carbamoyl-3-pyridyl alkanol, and large multifunctionalized pyrimidyl alkanols also act as highly efficient asymmetric autocatalysts in the addition of i-Pr2Zn to the corresponding aldehydes. The asymmetric autocatalysis of pyrimidyl alkanol can discriminate the chirality of various compounds. Chiral substances such as alcohols, amino acids, hydrocarbons, metal complexes, and heterogeneous chiral materials can act as chiral triggers for asymmetric autocatalysis to afford pyrimidyl alkanols with the corresponding absolute configuration of the initiator. This recognition ability of chiral compounds is extremely high, and chiral discrimination of a cryptochiral quaternary saturated hydrocarbon was established by applying asymmetric autocatalysis. By using the large amplification effect of the asymmetric autocatalysis, we can link various proposed origins of chirality with highly enantioenriched organic compounds in conjunction with asymmetric autocatalysis. Thus, a statistical fluctuation in ee of racemic compounds can be amplified to high ee by using asymmetric autocatalysis. Enantiomeric imbalance induced by irradiation of circularly polarized light can affect the enantioselectivity of asymmetric autocatalysis. The asymmetric autocatalysis was also triggered by the morphology of inorganic chiral crystals such as quartz, sodium chlorate, and cinnabar. Chiral organic crystals of achiral compounds also act as chiral initiators, and during the study of a crystal of cytosine, enantioselective chiral crystal phase transformation of the cytosine crystal was achieved by removal of the water of crystallization in an achiral monohydrate crystal. Enantioselective C-C bond formation was realized on the surfaces of achiral single crystals based on the oriented prochirality of achiral aldehydes. Furthermore, asymmetric autocatalysis of pyrimidyl alkanols is a highly sensitive reaction that can recognize and amplify the significantly small effect of a chiral compound arising solely from isotope substitution of hydrogen, carbon, and oxygen (D/H, (13)C/(12)C, and (18)O/(16)O). These examples show that asymmetric autocatalysis with an amplification of chirality is a powerful tool for correlating the origin of chirality with highly enantioenriched organic compounds. Asymmetric autocatalysis using two β-amino alcohols reveals a reversal of enantioselectivity in the addition of i-Pr2Zn to aldehyde and is one approach toward understanding the mechanism of asymmetric dialkylzinc addition, where heteroaggregates act as the catalytic species.

Mechanistic insights in the reversal of enantioselectivity of chiral catalysts by achiral catalysts in asymmetric autocatalysis.

A reversal of enantioselectivity induced by an achiral catalyst in association with a chiral catalyst was observed during asymmetric autocatalysis. This reversal of enantioselectivity is interpreted as a result of aggregation between the two catalysts, leading to another catalytic species. Both kinetic and enantioselectivity studies exhibit strong nonlinear effects and were shown to be very consistent with the formation of dimeric catalytic species. They brought some quantitative information about the structure and the catalytic properties of the mixed aggregate. This study also brings some new insights in the mechanism of the catalytic addition of dialkylzincs to aldehydes.

The Origins of Homochirality Examined by Using Asymmetric Autocatalysis

Pyrimidyl alkanol was found to act as an asymmetric autocatalyst in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde. Asymmetric autocatalysis of 2-alkynylpyrimidyl alkanol with an extremely low enantiomeric excess (ca. 0.00005% ee) exhibits enormous asymmetric amplification to afford the same compound with >99.5% ee. This asymmetric autocatalysis with amplification of ee has been employed to examine the validity of proposed theories of the origins of homochirality. Circularly polarized light, quartz, sodium chlorate, cinnabar, chiral organic crystals and spontaneous absolute asymmetric synthesis were considered as possible candidates for the origin of chirality; each could act as a chiral source in asymmetric autocatalysis. Asymmetric autocatalysis can discriminate the isotope chirality arising from the small difference between carbon (carbon-13/carbon-12) and hydrogen (D/H) isotopes. Cryptochiral compounds were also discriminated by asymmetric autocatalysis.

Generation of absolute controlled crystal chirality by the removal of crystal water from achiral crystal of nucleobase cytosine.

The enantioselective formation of chiral crystal of achiral nucleobase cytosine was achieved mediated by the crystal direction selective dehydration of crystal water in the achiral crystal of cytosine monohydrate (P21/c). Heat transfer from the enantiotopic face of the single crystal of cytosine monohydrate afforded the enantiomorphous crystal of anhydrous cytosine.

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.

Discrimination of cryptochirality in chiral isotactic polystyrene by asymmetric autocatalysis.

Cryptochiral isotactic polystyrene induces the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, affording the enantioenriched pyrimidyl alkanol with the corresponding absolute configuration to that of polystyrenes in conjunction with asymmetric autocatalysis.

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.

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.