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.     

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。     

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.     

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.     

Stochastic aspects of asymmetric autocatalysis and absolute asymmetric synthesis

The main goal of the present review is to collect in a unified framework the deterministic and stochastic models of emergence and amplification of chirality by mechanisms such as asymmetric autocatalysis and absolute asymmetric synthesis. Empirical approach and modeling have recently provided a good insight into these phenomena. Our groups in Italy and Hungary have a wide variety of expertise both in fields of experiments and modeling. In the last decade important results have been achieved, however, more experiments and more detailed deterministic and stochastic models are needed for a better understanding of details and significance of asymmetric autocatalysis and absolute asymmetric synthesis.     

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.     

不对称自动催化研究进展

不对称自动催化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, 在这类反应体系中, 催化剂自动放大倍增, 可简捷高效地制备高选择性的对映异构体, 在不对称催化和合成研究方面是一个新的领域。日本学者K. Soai 自90 年代以来, 在发现和研究高对映体选择性自动催化体系方面的重要贡献受到广泛关注。本文综述了近年来不对称自动催化反应的新进展。     

Role of the isopropyl group in asymmetric autocatalytic zinc alkylations

The amplifying asymmetric autocatalysis discovered by Soai and co-workers is dependent on the unique steric properties of the isopropyl group.     

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 without discrete optically active additives

By an adaptation of the asymmetric autocatalysis reactions of Soai, it was found that small enantiomeric excesses may be amplified to an arbitrary extent. When this process was applied 48 times to reactions in the absence of discrete optically active additives, all ultimately afforded substantial optical activity in the product. However, observations strongly suggest that most (and likely all) of these reactions are not true examples of absolute asymmetric synthesis. Rather, the ultimate optical activity arises from optically active impurities. Trace amounts of optically active materials may dominate the outcome of reactions involving asymmetric autocatalysis, and in the presence of opposite chiral influences a single enantiomer tends to take over a reaction. The possible implications of these observations to the origin of biological homochirality are noted.     

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 mediated by chiral crystal of achiral hippuric acid in conjunction with asymmetric autocatalysis

Enantiomorphous crystals composed of achiral hippuric acid, i.e., naturally occurring N-benzoylglycine, have been used successfully as chiral inducers in enantioselective synthesis in combination with asymmetric autocatalysis to afford the product with extremely high enantiomeric excess.     

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.     

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.     

Stochastic kinetic models of chiral autocatalysis: a general tool for the quantitative interpretation of total asymmetric synthesis

A continuous time discrete state stochastic kinetic approach is used to study various chiral autocatalytic models in which the possibility of total asymmetric synthesis arises. It is shown that this approach is superior to the deterministic approaches used earlier and is able to interpret many aspects of chiral autocatalysis. First-order autocatalysis, independently of further kinetic details of the system, leads to a unique final statistical distribution of enantiomers. Higher order autocatalysis, on the other hand, leads to a final state where one of the enantiomers is in overwhelming excess over the other. Criteria are postulated to differentiate between inherently stochastic phenomena in chiral autocatalytic reactions and irreproducibility because of insufficient control of external factors.     

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.     

Kinetic aspects of non-linear effects in asymmetric synthesis,catalysis, and autocatalysis

The Kagan ML_n models developed for rationalizing non-linear effects of catalyst enantiopurity have become a valuable mechanistic tool for probing complex asymmetric catalytic reactions. This work demonstrates how these models also provide clues about reactivity that may be used for further evidence to test a mechanistic hypothesis. Special considerations for probing non-linear effects in asymmetric synthesis using stoichiometric chiral auxiliaries and in asymmetric autocatalysis are highlighted in comparison with asymmetric catalysis.     

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.     

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 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.