Development of efficient chiral catalyst continues to be an important challenge in the fields of synthetic organic chemistry and medicinal chemistry. Although metal-based Lewis acid catalysts had been extensively studied for the activation of carbonyl group and imine, chiral Brønsted acid has emerged in the beginning of 21st century. We synthesized chiral phosphoric acid, derived from (R)-BINOL, and demonstrated its catalytic activity in the Mannich-type reaction as a chiral Brønsted acid in 2004. Chiral phosphoric acid functioned as bifunctional catalyst bearing both basic site and Brønsted acidic site. The 3,3’-substituents play an important role. Since then, chiral phosphoric acid catalysis has become a popular research area, and its utility has been remarkably expanded. In this article, we will describe the development of chiral phosphoric acid and recent progress of the chiral phosphoric acid catalysis from our research group, in particular following topics; 1) transfer hydrogenation reaction of ketimines by use of benzothiazoline as a hydrogen donor, and oxidative kinetic resolution of indolines, 2) Friedel-Crafts alkylation reaction of indoles, and 3) enantioselective synthesis of chiral biaryls by bromination and transfer hydrogenation. In addition, several tips for using chiral phosphoric acid are also described.

This article summarizes our recent studies on iridium-catalyzed asymmetric reactions realizing the high atom efficiency. Iridium complexes efficiently catalyzed asymmetric functionalization of aromatic compounds via directed C-H activation. Formal [3+2] annulation of ketimines with 1,3-dienes or alkynes gave the corresponding annulation products in high yields with high enantioselectivity. Branch-selective alkylation of aromatic compounds with vinyl ethers was efficiently catalyzed by Ir(I)/chiral diene complexes. Hydroacylation of bicyclic alkenes with salicylaldehydes also proceeded via acyl C-H bond activation. Meanwhile, asymmetric synthesis of heterocycles via C-O and C-N bond formation were also achieved. Annulation of salicylimines and α-oxocarboxamides with 1,3-dienes proceeded to give chromane and pyrrolidone derivatives, respectively. Asymmetric cyclization of alkenoic acids and alkenamides took place to give γ-lactones and γ-lactams, respectively.

A highly effective synthetic method via ruthenium catalyzed asymmetric hydrogenation was developed for (S)-methyl-2-(6-hydroxy-2,3-dihydrobenzofuran-3-yl)acetate, a key intermediate in the synthesis of the active pharmaceutical ingredient for GPR40/FFAR1 agonist, fasiglifam (TAK-875). In the 1st generation asymmetric hydrogenation, the cost ratio of a chiral amine ((S)-ADPP) to upgrade for enantiomer excess and the chiral ruthenium catalyst was high in overall manufacturing cost of fasiglifam. We tried to change to an inexpensive chiral amine ((R)-PEA) and reduce the chiral ruthenium catalyst amount. It was important to control the dissolved oxygen in solvent and to purify the substrate as a (R)-PEA salt. As a result, we successfully reduced the asymmetric catalyst amount to s/c 20,000 by application of the ruthenium catalyst and the changing substrate form under the tightly controlled conditions (2nd generation asymmetric hydrogenation). Finally, this manufacturing process was successfully performed at commercial scale.

Hydrolase-catalyzed dynamic kinetic resolution (DKR) of racemic secondary alcohols has made a significant progress in the last two decades, and this process has become one of the most convenient and practical methods to convert racemic alcohols into enantiopure compounds in up to 100% yields. Such DKR is performed using an integration of the hydrolase-catalyzed kinetic resolution of racemic alcohols and the in situ racemization of the remaining less reactive enantiomers by other catalysts, majority of which include metallic redox catalysts and oxovanadium compounds. This article mainly introduces the DKR of secondary alcohols by hydrolase-oxovanadium integrated catalysis developed by the author’s group. Some examples of their applications to asymmetric synthesis of natural products are also discussed.

Nine-membered E,Z-diallylic heterocycles 1 and [7]-orthocyclphenes 2 exhibit planar chirality at ambient temperature. Their stereochemical stabilities are highly dependent on substituent R¹ on the E-alkene, embedded heteroatom X in the ring, and ring size. Their planar chirality can be transformed into carbon central chirality without loss of enantiopurity. Therefore, they are useful chiral building blocks for biologically active chiral molecules and precursors for chiral reagents. The enantioenriched forms of 1 and 2 are available by optical resolution of racemate, and asymmetric synthesis based on enantioselective cyclization. Planar chiral dialkoxysilane 32 and ketone 33 were also developed.

The enantioselective synthesis of helicenes have been achieved via the rhodium-catalyzed [2+2+2] cycloaddition. The rhodium-catalyzed enantioselective intramolecular [2+2+2] cycloaddition of 2-naphthol-linked triynes afforded [7]helicenes with good yields and ee values. The rhodium-catalyzed enantioselective double intramolecular [2+2+2] cycloaddition of a 2-naphthol-linked hexayne also proceeded to give a [11]helicene-like molecule with high ee value, although the product yield was low. Not only the intramolecular reactions but also intermolecular ones were accomplished by combination of electron-rich tetraynes and electron-poor diynes to give [7]- and [9]helicenes, and hetero[7]helicenes in varying yields and ee values. Fluorescence quantum yields of thus synthesized helicenes were higher than unfunctionalized carbohelicenes and some of them exhibited excellent circular polarized luminescence (CPL) activity.

Since the pioneering work by Stoddart, Sauvage, and Feringa on the design and synthesis of molecular machines, to whom the 2016 Nobel Prize in Chemistry was awarded, various kinds of synthetic molecular machines have been developed. A helical structure, one of the essential structural motifs in biological systems, has the potential as a versatile structural component for constructing such a molecular machine, because of its spring-like shape that enables extension and contraction motions. We report here the recent progress in the synthesis, structures, and functions of artificial molecular springs based on single-or double-stranded helical oligomers and polymers that undergo an intriguing stimuli-responsive extension-contraction motion with maintaining their helical structures but with a change in the helical pitch. In particular, double-stranded spiroborate helicates with a one-handed helical sense exhibit a unique reversible elastic motion accompanied by a unidirectional twisting motion, thereby enabling a chiral molecular motion.

New functions of helical poly(quinoxaline-2,3-diyl)s (PQX) have been developed on the basis of highly efficient, dynamic induction of single-handed helical structure by using various chiral side chains along with incorporation of achiral functional monomer units. The efficiency and direction of the screw-sense induction are significantly dependent on chiral side chains, achiral side chains, solvents, and pressure according to normal and abnormal sergeants-and-soldiers effect. The dynamic nature of the helix induction allows sharp inversion of their helical sense between two solvents such as CHCl₃/1,1,2-trichloroethane, THF/t-butyl methyl ether, and even n-octane/cyclooctane. PQXs having functional units are utilized as chirality-switchable chiral catalysts and materials for emission/reflection of circularly polarized light. Chirality-amplifying asymmetric catalyst system is demonstrated on the basis of majority-rule effect on the induction of macromolecular helical structure.

Chirality appeared in interlocked systems such as catenanes, knots, and rotaxanes has attracted particular interest due to its possibility producing large and flexible asymmetric field, in addition to the switch function based on high mobility of the components. The exploration of new chiral molecules and systems is of great significance in association with their function and capability as chiral source, from viewpoint of vast stretch of chirality in many scientific fields. In this review, we first introduce the paradigm of the rotaxanes’ stereoisomerism, and then the recent advance on the synthesis of interlocked molecules, mainly of rotaxanes with mechanically planar chirality as one of molecular chiralities. Use of such rotaxanes as a chiral source in secondary structure control of polymers is also discussed as the first application of the mechanically planar chiral rotaxanes, with special emphasis on the dynamic helicity change of polyphenylacetylenes and poly(m-phenylene diethynylene) bearing the chiral pendant rotaxane group.

Conventionally, it has been considered that two-fold rotation and helix symmetry operations yield no generation of supramolecular chirality in organic crystals. However, such operations yield molecular assemblies whose supramolecular chirality can be easily recognized due to the multipoint approximation method. Stereochemistry tells us that such chirality originates from sliding and tilting among contacting molecules. Typically, facial molecules exhibit three different contacts; face-to-face, face-to-side and side-to-side, which are combined toward columnar molecular assemblies with three-axially anisotropic structures. The resulting chiral and helical columns form various bundles, enabling us to stereochemically imagine space groups involving multiple symmetry operations in crystallography. Among the operations, a selected one forms a preferential molecular column, and the remaining ones form the bundles. This new integrated insight for organic crystals would prompt us to understand stereochemical courses for chiral crystallization from achiral molecules as well as conglomerate formation from racemates.

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.

The use of theoretical calculations of circular dichroism (CD) and vibrational circular dichroism (VCD) spectroscopies for structural analysis has been becoming popular among organic chemists. In association with the conventional CD exciton chirality method and a recently-developed VCD exciton chirality method, proper use of CD and VCD spectroscopies should advance various studies related to chirality. This article briefly discusses the basics of structural analysis using theoretical calculations and the exciton chirality method of CD and VCD, with some tips and cautions for reliable spectral interpretation. The latter half of this article is dedicated to describing recent examples of the use of VCD for analyzing the configuration and conformation of small molecules, polymers, supramolecules, etc.

We briefly describe recent results obtained by using the generalized high-accuracy universal polarimeter abbreviated as G-HAUP. The γ-polymorph of an achiral glycine which crystallizes in space group P3₁ or P3₂ was found to exhibit laevorotatory or dextrorotatory, respectively. The chiroptical properties and optical anisotropies in chiral photomechanical crystals, salicylidenephenylethylamine crystals before and after UV light irradiation were revealed.

The crystalline sponge method is a new X-ray technique for single crystal structure analysis that does not require crystallization of target samples. We report here the application of this method to the absolute configuration determination of chiral compounds. As heavy atoms are already installed in the host framework, the Bijvoet method, which uses X-ray anomalous scattering, can be applied without incorporating heavy atoms in the samples. Target compounds are focused on (1) chiral small molecules produced by enantioselective (catalytic) reactions of current interest and (2) isolated natural products supplied by co-workers. In most on-going researches, absolute structure determination has been a bottle-neck, thus demonstrating that the crystalline sponge method considerably accelerates researches in these area. Trace amount analysis on microgram quantities enabled dramatic scale-down and cost-down in the isolation, purification, and structure determination of natural products.

The development of new chiral products in pharmaceutical, food and fragrance industries requires accurate and rapid evaluation of optical purity. Nowadays, polysaccharide-derived chiral stationary phases are considered as the first choice tools for the determination of enantiomeric excess by HPLC.

In the present article, a brief overview about coated type polysaccharide-derived chiral columns is introduced. From this basis, the main factors catalyzing the development and commercialization of the new generation of immobilized type chiral columns are described. This successful breakthrough was based on their excellent performance and separation abilities. In the last section, the scope of these new chromatographic products as packing materials, flash-columns and TLC formats are reviewed.

Chiral molecules exhibit different absorbance for left and right circularly polarized light. This phenomenon is called circular dichroism (CD). To measure CD spectra, a CD spectrometer alternately irradiates a sample with left and right circularly polarized light, and detects the difference in absorbance between the two cases.

CD spectroscopy is more sensitive and easier to perform than NMR or X-ray crystallography, and sample conditions such as the temperature and pH can be changed easily. Therefore, CD spectroscopy is suitable for measuring structural changes in chiral molecules while varying the sample environment. Because of the wide wavelength range from the far ultraviolet to the near infrared, biomolecules such as proteins, organic compounds and metal complexes can be targeted.