Chiral Molecular Science: How were the absolute configurations of chiral molecules determined? “Experimental results and theories”

Molecular chirality is a key concept in chemistry, bioscience, and molecular technology, like the invention of a light‐powered chiral molecular motor explained in this review. Thus, the primary research subject is how to determine the absolute configuration (AC) of chiral compounds. This review article focuses on the principle, theory, and practice of the nonempirical methods for determining ACs of chiral compounds, i.e., the Bijvoet method in X‐ray crystallography and the circular dichroism (CD) exciton chirality method, together with the historical aspects of AC determination. The theoretical equations of X‐ray crystallography and exciton CD spectroscopy are explained in detail, and these equations are useful for readers to understand the principle and mechanism of these methods. This review also focuses on the relative methods, where the internal reference with known AC is used and the relative configuration is determined by X‐ray crystallography and/or ¹H nuclear magnetic resonance (NMR) diamagnetic anisotropy method. In these cases, CSDP acid and MαNP acid are useful for the chiral resolution of racemic alcohols, where their diastereomeric esters are easily separable by high‐performance liquid chromatography (HPLC) on silica gel. Thus, these methods are useful for the preparation of enantiopure compounds and simultaneous determination of their ACs. In this review article, the above methods are explained mainly based on the author's own research results.     

Exciton coupling between enones: Quassinoids revisited

The electronic circular dichroism (ECD) spectra of two previously reported quassinoids containing a pair of enone chromophores are revisited to gain insight into the consistency and applicability of the exciton chirality method. Our study is based on time‐dependent Density Functional Theory calculations, transition and orbital analysis, and numerical exciton coupling calculations. In quassin ( 1 ) the enone/enone exciton coupling is quasi‐degenerate, yielding strong rotational strengths that account for the observed ECD spectrum in the enone π‐π* region. In perforalactone C ( 2 ) the nondegenerate coupling produces weak rotational strengths, and the ECD spectrum is dominated by other mechanisms of optical activity. We remark the necessity of a careful application of the nondegenerate exciton coupling method in similar cases.     

Evaluation of absolute configuration of naphthylphenyl-substituted oligosilanes by CD exciton chirality method

Absolute configurations of methylnaphthylphenyl-substituted oligosilanes, MeNpPhSi*SiMeR(1)R(2) [2 (R(1), R(2)=Me), 3 (R(1)=Me, R(2)=Ph), 4 (R(1), R(2)=Ph), and 5 (R(1)=Me, R(2)=SiMe(3))] were predicted by circular dichroism (CD) exciton chirality method. The sigma-pi conjugation effect of oligosilylene units (sigma-linkage) with pi-electron systems caused an intense red-shift of (1)L(a,Ph) transition band of the oligosilanes as shown in UV/VIS and made it possible to observe clear CD exciton chirality between the two aromatic chromophores on chiral silicon atom.     

Determination of absolute configurations by X-ray crystallography and 1H NMR anisotropy

To determine the absolute configurations of chiral compounds, many spectroscopic and diffraction methods have been developed. Among them, X-ray crystallographic Bijvoet method, CD exciton chirality method, and the combination of vibrational circular dichroism and quantum mechanical calculations are of nonempirical nature. On the other hand, X-ray crystallography using a chiral internal reference, and 1H NMR spectroscopy using chiral anisotropy reagents are relative and/or empirical methods. In addition to absolute configurational determinations, preparations of enantiopure compounds are strongly desired. As chiral reagents useful for both the preparation of enantiopure compounds by HPLC separation and the simultaneous determination of their absolute configurations, we have developed camphorsultam dichlorophthalic acid (CSDP acid) for X-ray crystallography and 2-methoxy-2-(1-naphthyl)propionic acid (MalphaNP acid) for 1H NMR spectroscopy. In this review, the principles and applications of these X-ray and NMR methods are explained using mostly our own data.     

Four new limonoids from the seeds of Chukrasia tabularis A. Juss.

Two new C-15 enolic acyl phragmalin-type limonoid orthoesters (1-2) which possessed a C-15-propionyl phragmalin skeleton and two new mexicanolide-type limonoids (3-4) were isolated from the ethanol extract of seeds of Chukrasia tabularis A. Juss. Their structures were established on the basis of spectroscopic analyses and electronic circular dichroism (ECD) exciton chirality method. Additionally, all of the compounds were screened against three human tumor cell lines MCF-7, SMMC-7721, and U2OS.     

Use of the exciton chirality method in the investigation of ligand-gated synthetic ion channels

The objective of this brief highlight is to point out the central role of the exciton chirality method to gain insights on the structural basis of the recently achieved ligand gating of synthetic ion channels. This unprecedented ligand gating was achieved with an equally unprecedented transmembrane rigid-rod pi-stack architecture that is designed to adopt a closed conformation with helically stacked naphthalenediimide (NDI) acceptors. The intercalation of the complementary electron-rich dialkoxynaphthalene ligands then stimulates the untwisting of the closed pi-helices into hollow barrel-stave supramolecules. During this helix-barrel transition, the angle between the transition moments of the exciton-coupled NDI chromophores decreases toward zero. The corresponding disappearance of the split CD provides, according to the exciton chirality method, the otherwise elusive experimental support that ligand-gated ion channel formation really occurs by this rationally designed helix-barrel transition.     

Hyperpatulols A–I,spirocyclic acylphloroglucinol derivatives with anti-migration activities from the flowers of Hypericum patulum

Nine new spirocyclic acylphloroglucinol derivatives, hyperpatulols A–I (1–9), were characterized from the flowers of Hypericum patulum. Their structures were elucidated by the basic analysis of the obtained spectroscopic data, and their absolute configurations were assigned by both the electronic circular dichroism (ECD) exciton chirality method and ECD calculation. The evaluation of their anti-migration effects on U2-OS human osteosarcoma cells showed that compound 4 exhibited moderate inhibitory activity in a dose-dependent manner. Further pharmacological studies revealed that 4 could regulate the expression of the proteins Vimentin and E-cadherin.     

Absolute configuration of 3-hydroxy acids formed by Stenotrophomonas maltophilia: application of multidimensional gas chromatography and circular dichroism spectroscopy.

The soil bacterium Stenotrophomonas maltophilia was found to transform various long-chain fatty acids selectively into 3-hydroxy fatty acids of shorter chain length. Their chiral evaluation was performed by multidimensional gas chromatography (MDGC) on modified cyclodextrin phase comparing the enantiodistribution of 1,3-diol formed without loss of stereochemical information from a representative microbial product with those of synthetic (3RS)- and (3S)-1,3-diols. Enantiomeric excesses of 84-98% (R) were determined for the microbially produced 3-hydroxy acids. In addition, the CD exciton chirality method was applied to determine their absolute configuration. Derivatization with 9-anthryldiazomethane and 2-naphthoylimidazole led to the required bichromophoric structures. Their CD spectra displayed a positive first Cotton effect around 254 nm and a negative second Cotton effect around 237 nm, which confirmed the (R)-configuration of the bacterial products.     

Determination of absolute configuration of 1,3-diols by the modified Mosher's method using their di-MTPA esters.

1,3-Diols are frequently involved in biologically important compounds and, therefore, determination of the stereochemistry of these structural elements, in particular those in acyclic systems, has been one of the focuses of attention in natural products chemistry. The modified Mosher's method, commonly used for the determination of the absolute configuration of secondary alcohols, was applied to determine the absolute configuration of 1,3-diols with their di-MTPA esters. Several epimeric pairs of syn- and anti-1,3-diols with known absolute configurations were converted to the corresponding di-MTPA esters and the iDelta;delta values were then calculated. For the acyclic syn-1,3-diols, the iDelta;delta values were systematically arranged as predicted from the basic concept of the modified Mosher's method, demonstrating that the method is valid for these compounds. In contrast, the iDelta;delta values were irregularly arranged for the acyclic anti-1,3-diols and, accordingly, this method is not valid for these cases. These results are complementary to those of the previously reported CD exciton chirality method and, hence, the combined use of the modified Mosher's method and the CD exciton chirality method can determine the absolute configuration of the acyclic 1,3-diols. Also, this method is successfully applicable to cyclic 1,3-diols irrespective of their relative stereochemistry.     

Structure and chiroptical properties of supramolecular flower pigments

Research over the last 30 years has shown that at physiological concentrations of ca. 5 x 10(-3) M, flower pigments composed of anthocyanins, either alone or complexed with flavone copigments, and frequently with metals, are self-assembled into non-covalent, chiral supramolecular complexes. This serves several biological functions including color stability, protection against UV radiation and provision for specific colors to attract insects for pollination. Self-association of the monomers takes place under conditions of molecular crowding by precise matching of the pi-pi stacking interactions of the aromatic chromophores and intermolecular hydrogen bonding between the attached sugars. The resulting handedness is controlled by the chiral information provided by the sugars joined glycosidically at certain positions around the periphery of the aromatic nuclei. This review gives an overview of (i) the physicochemical evidence including circular dichroism, (1)H NMR, and X-ray analysis for the structure and supramolecular chirality of these amphiphilic complexes, (ii) the role of the sugars on directing the chirality of the resulting supramolecules, (iii) the energetics of monomer association, and (iv) the possible influence of stacking chirality on insect pollination.     

Absolute configurational determination of an all-trans-retinal dimer isolated from photoreceptor outer segments

An all-trans-retinal (ATR) dimer (1) isolated from photoreceptor outer segments was found to have a stereogenic center at C13' flanked by tetraene (295 nm) and hexaenal (438 nm) chromophores. Analytical chiral HPLC (Chiralcel OD) revealed that the isolated retinoid had formed in 13% enantiomeric excess. Using a combination of (1)H-(1)H NOESY constraints, molecular modeling, and CD exciton coupling analysis, it was determined that the favored enantiomer was 13'(R). Three low-energy conformers of the 13'(S) model were found with MMFF/DFT and were used to calculate the CD spectrum of the ATR dimer (DeVoe method). The Boltzmann weighted spectrum was found to exhibit a positive exciton couplet, in excellent agreement with the experimental spectrum for the first eluted enantiomer. This further suggested that despite the large energy difference between the two interacting chromophores, the dominant source of optical activity in the CD spectrum is the nondegenerate exciton mechanism.     

Synthesis,Molecular Structure,and Chiroptical Properties of Dibenzylidene Derivatives of Bicyclo[3.3.1]nonane and Brexane

Synthesis of several enantiomerically pure unsaturated bicyclo[3.3.1]nonane and related brexane (tricyclo[4.3.0.0^3,7]nonane) derivatives bearing exocyclic benzylidene substituents from readily available (+)‐(1S,5S)‐bicyclo[3.3.1]nonane‐2,6‐dione was accomplished. Molecular geometry and chiroptical properties of compounds with enone and styrene chromophores were studied by X‐ray diffraction analysis, molecular modeling, and circular dichroism (CD) spectroscopy. Difunctional 3,7‐dibenzylidenebicyclo[3.3.1]nonanes, such as 2 and 7 , 8 , 9 , exhibited intense CD couplets, arising from the exciton coupling between the two unsaturated chromophores. The observed negative sign of the exciton couplets is congruent with the negative twist (negative chirality) defined by the two interacting transition dipoles. The sign of the Cotton effect corresponding to the π→π* transitions in the CD spectra of monoenone 4 and tricyclic brexane acetate 11 was correlated with the intrinsic dissymmetry (helicity) of the styrene chromophore. Chirality 27:728–737, 2015. © 2015 Wiley Periodicals, Inc.     

The enduring legacy of Koji Nakanishi's research on bioorganic chemistry and natural products. Part 1: Isolation,structure determination and mode of action

In this brief review on Koji Nakanishi's remarkable career in natural products chemistry, we have highlighted a number of his accomplishments that illustrate the broad diversity of his interests. These include the isolation, structure determination, and biological mechanism of action of many natural products including the triterpenoid pristimerin; the diterpenoid ginkgolides; insect and crustacean molting hormones; phytoalexins; the toxic red tide principle brevetoxin; the vanadium tunicate pigments; philanthotoxin from killer wasps; antisickling agents; mitomycin DNA adducts; insect antifeedants; a mitotic hormone, the small molecule fish attractants from the sea anemone; new isolation and purification technologies; molecular chemistry of vision; age-related macular degeneration; and the development of the exciton circular dichroism (CD) chirality method for microscale determination of absolute configuration of natural products and chirality of other chiral molecules and supramolecular assembly.     

Porphyrins and metalloporphyrins: versatile circular dichroic reporter groups for structural studies

During the last few years, porphyrins and metalloporphyrins have attracted widespread attention as chromophores for studies in circular dichroism (CD), an indispensable chiroptical tool for monitoring chiral interactions. This review summarizes the multifaceted properties of porphyrins and metalloporphyrins, powerful CD chromophores that are characterized by their intense and red-shifted Soret band, propensity to undergo pi-pi stacking, facile incorporation of metals, and ease in varying solubility. Such attributes make porphyrins one of the most attractive and sensitive chromophores used in CD studies. They offer possibilities for studying the stereochemistry of chiral porphyrin assemblies, large organic molecules, biopolymers, and compounds available in miniscule quantities. The tendency of porphyrins to undergo pi-pi stacking and zinc porphyrins to coordinate with amines enable the CD exciton chirality method to be extended to configurational assignments of flexible compounds containing only one stereogenic center. Various artificial porphyrin receptors have been synthesized for the recognition of biologically important chiral guests such as carbohydrates, amino acids, and their derivatives. The induced CD of the host porphyrin Soret band reflects the identity of guests and binding modes of host/guest complexation with high sensitivity.     

Chiroptical properties and conformation of chiral enamines of 2-(2′-pyrido,or quinolino) acetophenone

CD study of the chiral enamines 4-9 revealed the presence of the azastil-bene-like chromophore, and exciton coupling between this chromophore (A) and aromatic chromophore B . Coupled excitons in 5 and 8 suggest M (−) absolute conformation between chromophores A and B . © 1996 Wiley-Liss, Inc.     

Determination of the absolute configuration of Anisotome irregular diterpenes: application of CD and NMR methods

Several Anisotome diterpene derivatives were synthesized in an attempt to obtain a crystalline compound for X-ray analysis. Although we were unable to obtain a suitable crystal, the absolute configuration of the irregular diterpene skeleton was determined using two other techniques: a circular dichroism (CD) protocol based on a tetraarylporphyrin molecular tweezer that allowed prediction of the absolute stereochemistry on a microscale level, and a method employing differences in NMR shifts from derivatization of the naturally occurring acid 1 with enantiomers of a phenylglycine methyl ester (PGME) chiral anisotropic reagent. The excellent agreement between the CD and NMR methods led to the assignment of a 2S-absolute configuration for anisotomenoic acid 1.     

Trigonostemons G and H,dinorditerpenoid dimers with axially chiral biaryl linkage from Trigonostemon chinensis

Trigonostemons G and H, two novel dimeric dinorditerpenoids, were isolated from the stem barks of Trigonostemon chinensis. Their planar structures and relative configurations were established by extensive analysis of spectroscopic data. Trigonostemons G and H possess a homodimeric biaryl skeleton obtained from two rearranged chiral nonracemic abietane-type dinorditerpenes through an axially chiral biaryl 11,11′-linkage. Torsional scan and computation of the transition states were carried out to estimate the rotational energy barrier, and the axial chirality (aS) was determined by time-dependent density functional theory (TDDFT) electronic circular dichroism (ECD) calculations. The positive n-π* ECD transitions of the isolated carbonyl chromophore above 300 nm could be used to determine the central chirality of trigonostemon G independently by ECD calculations of the diastereomers.     

Synthesis of Diastereomeric Bicyclo[3.3.1]nonane Dibenzoyl Esters and Study of Their Chiroptical Properties

A synthesis of diastereomeric bicyclic dibenzoyl esters derived from enantiomerically pure (1S,5S)‐bicyclo[3.3.1]nonane‐2,6‐dione was accomplished. Molecules containing two benzoyl chromophores with different configuration in the bicyclic framework were obtained. Chiroptical properties of the synthesized enantiomerically pure molecules were studied. Diastereomeric esters exhibited exciton couplets in the circular dichroism (CD) spectra because of transannular interaction between non‐conjugated benzoate chromophores. The conformational effects and solvent impact on the exciton coupling were examined by CD spectroscopy. Theoretical computation of the CD spectra of diastereomers correctly reproduced the sign of the exciton couplets in the studied molecules, however, no major solvent dielectric constant influence and conformational effects per se on the exciton coupling was observed. Chirality 24:810–816, 2012. © 2012 Wiley Periodicals, Inc.     

Three Sesquiterpenoid Dimers from Chloranthus japonicus: Absolute Configuration of Chlorahololide A and Related Compounds

A novel sesquiterpenoid dimer, named multistalide C ( 1 ), together with two known congeners, shizukaols C ( 2 ) and D ( 3 ), was isolated from the whole plant of Chloranthus japonicus Sieb. The structures of compounds 1 , 2 , 3 were elucidated by extensive HR‐ESI‐MS, 1D, and 2D NMR spectroscopic analysis. Compounds 1 , 2 , 3 exhibited significant toxic effects on brine shrimp larvae (Artemia salina). The absolute configuration of 1 was established by CD/TDDFT calculations. The related compound chlorahololide A was also reinvestigated. The previous assignment of the absolute configuration of chlorahololide A and several related sesquiterpenoid dimers, based on an incorrect application of the exciton chirality method, is criticized. Chirality 28:158–163, 2015. © 2015 Wiley Periodicals, Inc.     

Supramolecular exciton chirality of carotenoid aggregates

The conventional organic chemistry concept of chirality relates to single molecules. This article deals with cases in which exciton chirality is generated by the interaction of associated carotenoids. The handed property responsible for exciton signals in these systems is due to the alignment of neighboring molecules held together by secondary chemical forces. Their mutual positions are characterized by the overlay angle. Experimental manifestation is obtained by spectroscopic studies on carotenoid aggregates. Compared to molecular spectra, both UV/visible and circular dichroism spectroscopic observations reveal modified absorption bands and induced Cotton effects of opposite sign (exciton couplets), respectively. A new term, "supramolecular exciton chirality," is suggested for these phenomena, allowing the detection of weak chemical interactions not readily accessible for experimental studies, although highly important in the mechanism of biological processes.