Achiral 2-pyridone and 4-aminopyridine act as chiral inducers of asymmetric autocatalysis with amplification of enantiomeric excess via the formation of chiral crystals.

Enantiomorphous crystals of achiral 2-pyridone and 4-aminopyridine served as sources of chirality, to induce the asymmetric autocatalysis of 5-pyrimidyl alkanol during the asymmetric addition of diisopropylzinc to the corresponding pyrimidine-5-carbaldehyde, that is, the Soai reaction. Following a significant amplification of enantiomeric excess through asymmetric autocatalysis, highly enantioenriched 5-pyrimidyl alkanol could be synthesized with their corresponding absolute configurations to those of chiral crystals of 2-pyridone and 4-aminopyridine.

Asymmetric Autocatalysis as an Efficient Link Between the Origin of Homochirality and Highly Enantioenriched Compounds.

Biological homochirality of essential components such as L-amino acids and D-sugars is prerequisite for the emergence, evolution and the maintenance of life. Implication of biological homochirality is described. Considerable interest has been focused on the origin and the process leading to the homochirality. Asymmetric autocatalysis with amplification of enantiomeric excess (ee), i.e., the Soai reaction, is capable to link the low ee induced by the proposed origins of chirality such as circularly polarized light and high ee of the organic compound. Absolute asymmetric synthesis without the intervention of any chiral factor was achieved in the Soai reaction.

Achiral amino acid glycine acts as an origin of homochirality in asymmetric autocatalysis.

Chiral crystals of the only achiral proteinogenic α-amino acid, glycine induced the asymmetric autocatalysis with amplification of enantiomeric excess (ee). The P31 crystals of γ-glycine, which display positive Cotton effect (CD) at around 215 nm, mediate the asymmetric autocatalysis to yield (R)-pyrimidyl alkanol with high ee. In contrast, the enantiomorphic P32 crystals, which display negative Cotton effect, afford (S)-alkanol after the significant amplification of ee by asymmetric autocatalysis.

Asymmetric autocatalysis. Chiral symmetry breaking and the origins of homochirality of organic molecules.

Biological homochirality, such as that of l-amino acids, has been a puzzle with regards to the chemical origin of life. Asymmetric autocatalysis is a reaction in which a chiral product acts as an asymmetric catalyst to produce more of itself in the same absolute configuration. 5-Pyrimidyl alkanol was found to act as an asymmetric autocatalyst in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde. Asymmetric autocatalysis of 2-alkynyl-5-pyrimidyl alkanol with an extremely low enantiomeric excess of ca. 0.00005% exhibited significant asymmetric amplification to afford the same pyrimidyl alkanol with >99.5% enantiomeric excess and with an increase in the quantity of the same compound. We have employed asymmetric autocatalysis to examine the origin of homochirality. Asymmetric autocatalysis triggered by circularly polarized light, chiral minerals such as quartz, chiral organic crystals composed of achiral compounds gave highly enantioenriched pyrimidyl alkanol with absolute configurations corresponding with those of the chiral triggers. Absolute asymmetric synthesis without the intervention of any chiral factor was achieved. Chiral isotopomers acted as chiral triggers of asymmetric autocatalysis.

Point-to-Point Ultra-Remote Asymmetric Control with Flexible Linker.

An ultra-remote intramolecular (point-to-point) asymmetric control through 38 bonds (1,39-asymmetric induction) has been achieved by using the principle of direct supramolecular orientation of catalytic and reactive moieties in asymmetric autocatalysis. We found the highly stereoselective diisopropylzinc addition reaction using designed molecules possessing pyrimidine sites at each terminal of a conformationally flexible simple methylene chain.

Reversal of the sense of enantioselectivity between 1- and 2-aza[6]helicenes used as chiral inducers of asymmetric autocatalysis.

Reversal of the sense of enantioselectivity was observed between 1-aza[6]helicene 2 and 2-aza[6]helicene 3 employed as chiral inducers of asymmetric autocatalysis of pyrimidyl alkanol. In the presence of (P)-(+)-1-aza[6]helicene 2, the reaction of pyrimidine-5-carbaldehyde 1 with diisopropylzinc afforded, in conjunction with asymmetric autocatalysis, (S)-pyrimidyl alkanol 4 with high ee. Surprisingly, the reaction in the presence of (P)-(+)-2-aza[6]helicene 3 gave the opposite enantiomer of (R)-alkanol 4 with high ee. In the same manner, (M)-(-)-2 and (M)-(-)-3 afforded (R)- and (S)-alkanol 4, respectively. The sense of enantioselectivity is controlled not only by the helicity of the azahelicene derivatives but also by the position of the nitrogen atom.

Unusual reversal of enantioselectivity in the asymmetric autocatalysis of pyrimidyl alkanol triggered by chiral aromatic alkanols and amines.

Temperature dependent inversion of enantioselectivity in asymmetric catalysis is an interesting and somewhat unusual phenomenon. We have observed temperature dependent inversion of enantioselectivity in the asymmetric autocatalysis reaction when triggered by a wide scope of enantioenriched alcohols and amines. The addition reaction of diisopropylzinc to pyrimidine-5-carbaldehyde in the presence of enantiopure alcohols or amines affords the pyrimidyl alkanol product at 0 °C with high ee. However, lowering the reaction temperature to -44 °C affords the opposite enantioselectivity.

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

Achiral inorganic gypsum (CaSO4 ⋅2 H2 O) 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.

Can the analyte-triggered asymmetric autocatalytic Soai reaction serve as a universal analytical tool for measuring enantiopurity and assigning absolute configuration?

An investigation is reported on the use of the autocatalytic enantioselective Soai reaction, known to be influenced by the presence of a wide variety of chiral materials, as a generic tool for measuring the enantiopurity and absolute configuration of any substance. Good generality for the reaction across a small group of test analytes was observed, consistent with literature reports suggesting a diversity of compound types that can influence the stereochemical outcome of this reaction. Some trends in the absolute sense of stereochemical enrichment were noted, suggesting the possible utility of the approach for assigning absolute configuration to unknown compounds, by analogy to closely related species with known outcomes. Considerable variation was observed in the triggering strength of different enantiopure materials, an undesirable characteristic when dealing with mixtures containing minor impurities with strong triggering strength in the presence of major components with weak triggering strength. A strong tendency of the reaction toward an 'all or none' type of behavior makes the reaction most sensitive for detecting enantioenrichment close to zero. Consequently, the ability to discern modest from excellent enantioselectivity was relatively poor. While these properties limit the ability to obtain precise enantiopurity measurements in a simple single addition experiment, prospects may exist for more complex experimental setups that may potentially offer improved performance.

Asymmetric Induction by a Nitrogen 14 N/15 N Isotopomer in Conjunction with Asymmetric Autocatalysis.

Chirality arising from isotope substitution, especially with atoms heavier than the hydrogen isotopes, is usually not considered a source of chirality in a chemical reaction. An N2 ,N2 ,N3 ,N3 -tetramethyl-2,3-butanediamine containing nitrogen (14 N/15 N) isotope chirality was synthesized and it was revealed that this isotopically chiral diamine compound acts as a chiral initiator for 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 ß-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.

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.

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.

Self-replication and amplification of enantiomeric excess of chiral multifunctionalized large molecules by asymmetric autocatalysis.

Self-replication of large chiral molecular architectures is one of the great challenges and interests in synthetic, systems, and prebiotic chemistry. Described herein is a new chemical system in which large chiral multifunctionalized molecules possess asymmetric autocatalytic self-replicating and self-improving abilities, that is, improvement of their enantioenrichment in addition to the diastereomeric ratio. The large chiral multifunctionalized molecules catalyze the production of themselves with the same structure, including the chirality of newly formed asymmetric carbon atoms, in the reaction of the corresponding achiral aldehydes and reagent. The chirality of the large multifunctionalized molecules controlled the enantioselectivity of the reaction in a highly selective manner to construct multiple asymmetric stereogenic centers in a single reaction.

Asymmetric autocatalysis triggered by oxygen isotopically chiral glycerin.

Chiral (S)- and (R)-(18)O-glycerin induces enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde, and the subsequent asymmetric autocatalysis affords (R)- and (S)-pyrimidyl alkanol with high enantiomeric excess, respectively.

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.

Circular dichroism spectroscopy of catalyst preequilibrium in asymmetric autocatalysis of pyrimidyl alkanol.

Mechanistic understanding of the asymmetric autocatalysis of pyrimidyl alkanol is a highly attractive and challenging topic due to its unique feature of amplification of enantiomeric excess. Circular dichroism spectroscopic analysis of this reaction allows monitoring of the structual changes of possible catalyst precursors in the solution state and shows characteristic temperature and solvent dependence. TD-DFT calculations suggest that these spectral changes are induced by a dimer-tetramer equilibrium of zinc alkoxides.

Asymmetric autocatalysis triggered by triglycine sulfate with switchable chirality by altering the direction of the applied electric field.

Triglycine sulfate (TGS) acts as a chiral trigger for asymmetric autocatalysis with amplification of enantiomeric excess, i.e., the Soai reaction. Therefore, molecular chirality of highly enantioenriched organic compounds is controlled by a ferroelectric crystal TGS, whose polarization is altered by an electric field.

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 (P2(1)/c). Heat transfer from the enantiotopic face of the single crystal of cytosine monohydrate afforded the enantiomorphous crystal of anhydrous cytosine.

Asymmetric autocatalysis induced by chiral crystals of achiral tetraphenylethylenes.

The achiral hydrocarbon tetraphenylethylene crystallizes in enantiomorphous forms (chiral space group: P2(1)) 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.