Absolute Asymmetric Synthesis Research Articles

Asymmetric synthesis of inositol derivatives

Both the enantiomers of racemic 4-O-tosyl-6-O-benzyl-myo-inositol-1,3,5-orthoformate (2) were isolated by preferential crystallization and used to synthesize several enantiomeric myo-inositol derivatives - natural ononitol, natural laminitol, precursors for myo-inositol phosphates and an oxabicyclo [2.2.1] heptane derivative. This work demonstrates the potential of the enantiomeric tosylates D2 and L2 to serve as versatile starting materials for the absolute asymmetric synthesis of inositol derivatives and other natural products from symmetric myo-inositol since no optically active molecular entity was required for the resolution of 2.

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.

Chance and Necessity in the Evolution of Matter to Life: A Comprehensive Hypothesis

Specialists in several branches of life sciences are trying to solve, piece by piece, the immensely complex puzzle of the origin of life. Some parts of the puzzle seem to appear with a rather high degree of clarity, while others remain totally obscure. We cannot be sure that life emerged only on our Earth, but we believe that the presence of large amounts of water in its liquid state is absolutely essential for the emergence and evolution of living matter. We can also assume that the latter exploits everywhere the same light elements, mainly C, H, O, N, S, and P, and somehow manipulates the same simple monomeric and polymeric organic compounds, such as alpha-amino acids, carbohydrates, nucleic bases, and surface-active carboxylic acids. The author contributes to the field by stating that all fundamental particles of our matter are “homochiral” and predominantly produce in an absolute asymmetric synthesis amino acids of L-configuration and carbohydrates of D-series. Another important point is that free atmospheric oxygen mainly stems from the photolysis of water molecules by cosmic irradiation and is not necessarily bound to living organisms on the planet.

Solvent-Driven Chirality Switching of a Pillar[4]arene[1]quinone Having a Chiral Amine-Substituted Quinone Subunit.

Several new chiral pillar[4]arene[1]quinone derivatives were synthesized by reacting pillar[4]arene[1]quinone (EtP4Q1), containing four 1,4-diethoxybenzene units and one benzoquinone unit, with various chiral amines via Michael addition. Due to the direct introduction of chiral substituents on the rim of pillar[n]arene and the close location of the chiral center to the rim of EtP4Q1, the newly prepared compounds showed unique chiroptical properties without complicated chiral resolution processes, and unprecedented high anisotropy factor of up to −0.018 at the charge transfer absorption band was observed. Intriguingly, the benzene sidearm attached pillar[4]arene[1]quinone derivative 1a showed solvent- and complexation-driven chirality inversion. This work provides a promising potential for absolute asymmetric synthesis of pillararene-based derivatives.

Absolute Asymmetric Synthesis Involving Chiral Symmetry Breaking in Diels–Alder Reaction

Efficient generation and amplification of chirality from prochiral substrates in the Diels–Alder reaction (DA reaction) followed by dynamic crystallization were achieved without using an external chiral source. Since the DA reaction of 2-methylfuran and various maleimides proceeds reversibly, an exo-adduct was obtained as the main product as the reaction proceeded. From single crystal X-ray structure analysis, it was found that five of ten exo-adducts gave conglomerates. When 2-methylfuran and various maleimides with a catalytic amount of TFA were reacted in a sealed tube, the exo-DA adducts were precipitated from the solution, while the reaction mixtures were continuously ground and stirred using glass beads. Deracemization occurred and chiral amplification was observed for four of the substrates. Each final enantiomeric purity was influenced by the crystal structure, and when enantiomers were included in the disorder, they reached an enantiomeric purity reflecting the ratio of the disorder. The final ee value of the 3,5-dimethylphenyl derivative after chiral amplification was 98% ee.

Demystifying the asymmetry-amplifying, autocatalytic behaviour of the Soai reaction through structural, mechanistic and computational studies.

The Soai reaction has profoundly impacted chemists’ perspective of chiral symmetry breaking, absolute asymmetric synthesis and its role in the origin of biological homochirality. Herein, we describe the unprecedented observation of asymmetry amplifying autocatalysis in the alkylation of 5-(trimethylsilylethynyl)pyridine-3-carbaldehyde using diisopropylzinc. Kinetic studies with a surrogate substrate and spectroscopic analysis of a series of zinc-alkoxides that incorporate specific structural mutations reveal a ‘pyridine-assisted cube escape’. The new tetrameric cluster functions as a catalyst that activates the substrate through a two point binding mode and poises a coordinated diisopropylzinc moiety for alkyl group transfer. Transition-state models leading to both the homochiral and heterochiral products were validated by density functional theory calculations. Moreover, experimental and computational analysis of the heterochiral complex provides a definitive explanation for the non-linear behavior of this system. Our deconstruction of the Soai system reveals the structural logic for autocatalyst evolution, function and substrate compatibility – a central mechanistic aspect of this iconic transformation.

Absolute Asymmetric Synthesis of an Aspartic Acid Derivative from Prochiral Maleic Acid and Pyridine under Achiral Conditions.

The asymmetric synthesis of an aspartic acid derivative, N-succinopyridine, from prochiral starting materials involving dynamic enantioselective crystallization was accomplished without using any external chiral source. The aza-Michael addition reaction of prochiral maleic acid and pyridine afforded racemic conglomerate N-succinopyridine in water. Continuous stirring of the suspension of the reaction mixture with acetic acid promoted gradual deracemization to afford a crystal with an excellent optical purity of 99 % in 71 % yield.

Energy threshold for chiral symmetry breaking in molecular self-replication.

The homochirality of biological molecules (right-handed sugars and left-handed amino acids) is a signature of life. Extensive research has been devoted to understanding how enrichment of one enantiomer over the other might have emerged from a prebiotic world. Here, we use experimental data from the model Soai autocatalytic reaction system to evaluate the energy required for symmetry breaking and chiral amplification in molecular self-replication. One postulate for the source of the original imbalance is the tiny difference in energy between enantiomers due to parity violation in the weak force. We discuss the plausibility of parity violation energy difference coupled with asymmetric autocatalysis as a rationalization for absolute asymmetric synthesis and the origin of the homochirality of biological molecules. Our results allow us to identify the magnitude of the energy imbalance that gives rise to directed symmetry breaking and asymmetric amplification in this autocatalytic system.

Self-Replication of Chiral α-Amino Acids in Strecker-Type Synthesis via Asymmetric Induction and Amplification of Their Own Chiral Intermediate α-Aminonitriles

Abstract Self-replication is one of the essential characteristics of life, therefore, chemical reaction, in which biologically related chiral enantioenriched compounds can promote their own production, is an attractive challenge in broad scientific fields. Here, we found asymmetric Strecker-type synthesis, in which chiral l- and d-α-amino acids enantioselectively induced the formation and amplification of their own chiral intermediates l- and d-α-aminonitriles in solid state, respectively. Thus, after the hydrolysis of aminonitriles, enantioenriched amino acids with the same structure and the same absolute configuration as that of the original compounds could be replicatively produced with improvement of enantiomeric excess. Following our first report on the replication of α-(p-tolyl)glycine, here we found that the enantiomer of α-(1-naphthyl)glycine and α-(o-tolyl)glycine can also replicatively multiply in the Strecker-type synthesis via the amplification of the corresponding aminonitriles. From the viewpoint of the absolute asymmetric Strecker-type amino acid synthesis, spontaneous formation, amplification and multiplication, i.e., enantioselective reactive crystallization of α-aminonitriles will be discussed.

Role of Asymmetric Autocatalysis in the Elucidation of Origins of Homochirality of Organic Compounds

Pyrimidyl alkanol and related compounds were found to be asymmetric autocatalysts in the enantioselective addition of diisopropylzinc to pyrimidine-5-carbaldehyde and related aldehydes. In the asymmetric autocatalysis with amplification of enantiomeric excess (ee), the very low ee (ca. 0.00005%) of 2-alkynyl-5-pyrimidyl alkanol was significantly amplified to >99.5% ee with an increase in the amount. By using asymmetric autocatalysis with amplification of ee, several origins of homochirality have been examined. Circularly polarized light, chiral quartz, and chiral crystals formed from achiral organic compounds such as glycine and carbon (13C/12C), nitrogen (15N/14N), oxygen (18O/16O), and hydrogen (D/H) chiral isotopomers were found to act as the origin of chirality in asymmetric autocatalysis. And the spontaneous absolute asymmetric synthesis was also realized without the intervention of any chiral factor.

Viedma Ripening of Chiral Coordination Polymers Based on Achiral Molecules

When the chiral coordination polymers were composed of achiral molecules, the deracemization of the bulk product remains a great challenge if without any chiral induction. The Viedma ripening theory was adopted herein to help the achievement of mirror symmetry breaking for the bulk chirality of two chiral coordination polymers. The enantiomeric excess of the bulk chirality for the first compound is about 100%, which means absolute asymmetric synthesis. The deracemization degree of the bulk chirality for the second compound fluctuates occasionally. Further study has discussed the different deracemization degree of the bulk chirality for two compounds with the consideration of enantioselective incorporation in crystal cluster.

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.

Formation of enantioenriched alkanol with stochastic distribution of enantiomers in the absolute asymmetric synthesis under heterogeneous solid-vapor phase conditions.

Among several theories proposed for the origin of homochirality, absolute asymmetric synthesis is unique because it produces chiral compounds without the intervention of any chiral factor. Here we report on the kinetically controlled heterogeneous solid-vapor phase absolute asymmetric synthesis in conjunction with asymmetric autocatalysis with amplification of chirality. Each reaction, carried out in a test tube, between achiral powder crystals of pyrimidine-5-carbaldehyde and the vapor of diisopropylzinc, is controlled kinetically to afford either (S)- or (R)-pyrimidyl alkanol.

Absolute asymmetric Strecker synthesis in a mixed aqueous medium: reliable access to enantioenriched α-aminonitrile.

Without using chiral sources, the Strecker reaction of achiral hydrogen cyanide, p-tolualdehyde and benzhydrylamine gave enantioenriched l- or d-N-benzhydryl-α-(p-tolyl)glycine nitriles with up to >99% ee in a mixed solvent of water and methanol. Therefore, total spontaneous resolution of α-aminonitriles could occur through a prebiotic mechanism of α-amino acid synthesis. Moreover, it was demonstrated that the repetition of partial dissolution and crystallization of a suspended conglomerate of aminonitrile under solution-phase racemization could generate the enantiomeric imbalance to afford, in combination with the amplification of chirality, an enantioenriched product in every case. Among the 73 experiments that were carried out, d- and l-enriched isomers occurred 36 and 37 times, respectively. This stochastic behavior, under achiral or racemic starting conditions, meets the requirements of the spontaneous absolute asymmetric Strecker synthesis. The implications of the present results for the origin of chirality of α-amino acids are discussed.

Circular Dichroism Photoswitching with a Twist: Axially Chiral Hemiindigo.

Chiroptical properties play a crucial role not only for molecular structures and their functions but also for advanced applications such as molecular sensing, absolute asymmetric synthesis, or information processing and storage. Manipulating chiroptical characteristics in a predictable and reversible fashion by outside means is therefore a highly desirable option to enhance the functions and reporting abilities of a molecular system. Herein, we present axially chiral hemiindigo photoswitches showing unusual chiroptical changes upon visible-light irradiation. While absorption remains high throughout the spectrum, the corresponding ECD signals can be reversibly erased and reestablished in an ON/OFF manner upon photoswitching. Taken together with exceptionally high thermal bistabilities, leading to half-lives of the metastable states up to 3400 years at ambient temperature, and high photoswitching quantum yields these chiral hemiindigos offer unique possibilities for, e.g., smart molecule, photonic materials, or sensing applications.

The Strecker reaction coupled to Viedma ripening: a simple route to highly hindered enantiomerically pure amino acids.

The Strecker reaction is broadly used for the preparation of α-amino acids. However, control of enantioselectivity remains challenging. We here couple the Strecker reaction to Viedma ripening for the absolute asymmetric synthesis of highly sterically hindered α-amino acids. As proof-of-principle, the enantiomerically pure α-amino acids tert-leucine and α-(1-adamantyl)glycine were obtained.

Frozen Chirality of Tertiary Aromatic Amides: Access to Enantioenriched Tertiary α-Amino Acid or Amino Alcohol without Chiral Reagent.

One of the fundamental and intriguing aspects of life is the homochirality of the essential molecules. In this field, the absolute asymmetric synthesis of α-amino acids is a major challenge. Herein, we report access, by chemical means, to tertiary α-amino acid derivatives in up to 96 % ee without using any chiral reagent. In our strategy, the dynamic axial chirality of tertiary aromatic amides is frozen in a crystal and is responsible for the stereoselectivity of the subsequent steps. Furthermore, we could control the configuration of the final product by manually sorting and selecting the initial crystals. Based on vibrational circular dichroism studies, we could rationalize the observed stereoselectivity.

Mechanically Induced Homochirality in Nucleated Enantioselective Polymerization.

Understanding how biological homochirality may have emerged during chemical evolution remains a challenge for origin of life research. In keeping with this goal, we introduce and solve numerically a kinetic rate equation model of nucleated cooperative enantioselective polymerization in closed systems. The microreversible scheme includes (i) solution-phase racemization of the monomers, (ii) linear chain growth by stepwise monomer attachment, in both nucleation and elongation phases, and (iii) annealing or fusion of homochiral chains. Mechanically induced breakage of the longest chains maintains the system out of equilibrium and drives a breakage-fusion recycling mechanism. Spontaneous mirror symmetry breaking can be achieved starting from small initial enantiomeric excesses due to the intrinsic statistical fluctuations about the idealized racemic composition. The subsequent chiral amplification confirms the model's capacity for absolute asymmetric synthesis, without chiral cross-inhibition and without explicit autocatalysis.

有機結晶のキラリティーを利用した不斉合成法の開発

Asymmetric synthesis from achiral starting materials using only crystal chirality under absolutely achiral conditions-that is, absolute asymmetric synthesis-has been investigated by many methods, including solid-state photochemical reactions, asymmetric reactions using frozen chirality, and dynamic crystallization (total spontaneous resolution). Dynamic crystallization using racemic conglomerate crystals involved that an enantiomerically enriched solid state could be achieved through crystallization from a solution in which chiral molecules could rapidly racemize. Many such examples resulted in total optical resolution by deracemization, selectively leading to single-handed molecules. Furthermore, a combined methodology for generating a chiral center from achiral materials, involving dynamic crystallization or attrition-enhanced deracemization, was recently developed. These examples demonstrate the high potential of this new category of absolute asymmetric synthesis.

Asymmetric Synthesis Using Chiral Crystals of Coumarin-3-carboxamides and Carbenoids

Unprecedented absolute asymmetric synthesis was carried out using frozen chirality derived from chiral crystals of achiral coumarin-3-carboxamide and carbenoids. An enantioselective cycloaddition reaction with a sulfur ylide gave an optically active cyclopropane up to 97% ee. Furthermore, a cycloaddition reaction with dichlorocarbene gave dihydrofuran in 93% ee. Nucleophilic addition of ylide or carbene occurs from the side of the carbonyl oxygen atom to avoid steric hindrance of substituents on the nitrogen atom.