Synthesis and circular dichroism studies of N,N-bis(2-quinolylmethyl)amino acid Cu(II) complexes: determination of absolute configuration and enantiomeric excess by the exciton coupling method

We report a method to determine the absolute configuration of alpha-amino acids by exciton coupled circular dichroism (ECCD). Naturally occurring amino acids were successfully derivatized with 2-bromomethylquinoline. Complexation of these conformationally flexible ligands with Cu(II) salts yielded defined propeller-like structures. The direction of the twist (i.e., the relative orientation of the chromophores to each other) is governed by the asymmetric amino acid carbon center. The transition moments of the chromophores couple and yield a bisignate circular dichroism spectrum, the sign of which corresponds to the absolute configuration of the chiral center of the amino acid. Enantiomeric excess (e.e.) of amino acid derivatives is linearly related to the differential extinction coefficient Delta(epsilon) and can be assessed easily utilizing a standard curve. This efficient, sensitive technique requires low analyte concentrations, offers several advantages over established methods, and could be applied in medicinal, pharmaceutical, or chemical retail and manufacturing industry.     

Resolution of 1- and 2-naphthylmethoxyacetic acids,NMR reagents for absolute configuration determination,by use of L-phenylalaninol

Racemic 1- and 2-naphthylmethoxyacetic acids (1NMA and 2NMA), the chiral anisotropic reagents used for absolute configuration determination of chiral secondary alcohols and primary amines, were conveniently resolved to enantiomers (>99% ee) by condensation with L-phenylalaninol (2-amino-3-phenylpropanol), chromatographic separation of the diastereomers, and hydrolysis. This method enables large-scale preparation of enantiomeric 1NMA and 2NMA.     

Absolute stereochemical determination of 1,2-diols via complexation with dinaphthyl borinic acid

Rapid derivatization of chiral 1,2-diols with dinaphthyl borinic acid ( DBA ) leads to a cyclic boronate, enabling the absolute stereochemical prediction via exciton-coupled circular dichroic (ECCD) of the naphthyl groups. Aryl- and alkyl-substituted 1,2-diols derivatized with DBA yield a predictable ECCD, which is also in agreement with theoretical predictions derived from computationally minimized structures.     

Enhancement of exciton coupled circular dichroism with sterically encumbered bis-porphyrin tweezers

Porphyrin tweezers have been successfully used as hosts for the absolute stereochemical determination of a variety of chiral compounds. A set of new porphyrin tweezers with substituted aryl groups on the meso position of the porphyrin rings have been synthesized. The modified tweezers are used as hosts for the stereochemical determination of chiral diamines and carrier-derivatized alpha-chiral carboxylic acids in order to monitor the influence of the various substitutions of the aryl group on the amplitude and sign of the ECCD couplet. t-Butyl substitution at the meta positions of the porphyrin's meso phenyl substituents leads to enhanced ECCD amplitudes.     

Chiral Amine Enantiomeric Excess Determination Using Self‐Assembled Octahedral Fe(II)‐Imine Complexes

A receptor assembly composed of iron(II) triflate and pyridine‐2,6‐dicarbaldehyde was used to determine the enantiomeric excess (ee) of alpha‐chiral primary amines using circular dichroism spectroscopy. The alpha chiral amines condense with the dialdehyde to form a diimine, which forms a 2:1 octahedral complex with iron(II). The ee values of unknown concentrations of alpha‐chiral amines were determined by constructing calibration curves for each amine and then measuring the ellipticity at 600 nm. This improves our previously reported assay for ee determination of chiral primary amines by further increasing the wavelength at which CD is measured and reducing the absolute error of the assay. Chirality 27:294–298, 2015. 2015 Wiley Periodicals, Inc.     

Chiroptical properties of 2,3-dihydrobenzo[b]furan and chromane chromophores in naturally occurring O-heterocycles

The correlation between the helicity (absolute conformation) of the O-heterocyclic ring of chiral 2,3-dihydrobenzo[b]furan (1) and chromane (2) derivatives and their (1)L(b) band CD was investigated. The same helicity rule was found for both unsubstituted chromophores: P/M helicity of the heterocyclic ring leads to a negative/positive CD within the (1)L(b) band. While the substitution of the fused benzene ring by achiral substituents does not change this helicity rule for the chromane chromophore, it leads to its inversion for the 2,3-dihydrobenzo[b]furan chromophores. On the basis of these observations, the published absolute configurations of natural flavonol and pterocarpan derivatives were confirmed and the configurational assignments of several natural neolignans revised.     

Mass Spectra of Volatile Sulfur Compounds in Foods

The absolute configurations of twelve α-aryl and α,β-diarylalkylamines were studied as N-acyl derivatives by circular dichroism (CD) measurements and by gas chromatography (GC).

The signs of Cotton effects for the S-configuration around 260 nm were positive and those around 210 nm were negative, although some exceptions were found due to the substituents on the benzene nuclei. In contrast, the GC behavior was considered less sensitive to the substituents on the benzene nuclei, and the elution orders were an R-before S-configuration consistently on a chiral OA-300 column. The absolute configurations of some amines were estimated in this study. GC as well as CD measurements could be a promising method for the assignment of the absolute configuration.     

CD‐sensitive Zn‐porphyrin tweezer host‐guest complexes,part 1: MC/OPLS‐2005 computational approach for predicting preferred interporphyrin helicity

This article describes a computational study on dimeric zinc porphyrin tweezer complexes with primary/secondary amines and secondary alcohols that validates the use of Optimized Potential for Liquid Simulations (OPLS‐2005) as the lead computational choice for assisting the tweezer methodology in the absolute configurational assignment of organic compounds. A supramolecular, microscale approach known as the tweezer method has been widely applied in the past decade for determining the absolute configuration of chiral substrates that are difficult to study by other readily available methods. The method relies on a host/guest complexation mechanism between a porphyrin tweezer moiety and a substrate, after its conversion into a bidentate conjugate. The formation of 1:1 complexes is a stereodifferentiating process: upon complexation, the originally achiral tweezer adopts a preferential interporphyrin helicity, dictated by the absolute configuration of the chiral substrate. By correctly predicting the sign of the interporphyrin helicity in the complex, OPLS‐2005 provides a correlation between the observed circular dichroism (CD) signal and the absolute configuration of the substrate. It also offers a great degree of insight into the structural factors responsible for chiral recognition and the amplitude of exciton couplets. Moreover, the preferential binding sites between the Zn‐tweezer and secondary amine conjugates were revealed by using the new computational approach. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

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.     

Synthesis of enantiopure phthalides including 3-butylphthalide, a fragrance component of celery oil, and determination of their absolute configurations

Enantiopure phthalides 2 and 5-8 were synthesized via enantioresolution of the corresponding alcohols with a chiral auxiliary of camphorsultam dichlorophthalic acid, (1S,2R,4R)-(-)-CSDP acid 3, followed by solvolysis with KOH in MeOH and the catalytic oxidation of chiral glycols with iridium complex 28. The absolute configurations of phthalides 2 and 5-8 were determined by applying the (1)H-NMR anisotropy method of MalphaNP acid (4), 2-methoxy-2-(1-naphthyl)propionic acid, to the chiral synthetic precursory alcohols. In the case of 3-phenylphthalide (R)-(-)-7, the absolute configuration determined by the (1)H-NMR anisotropy method using MalphaNP acid 4 agreed with that by the X-ray crystallographic method. By applying these methods, 3-butylphthalide (S)-(-)-2, a fragrance component of essential oil of celery, has been synthesized in an enantiopure form, and its absolute configuration was unambiguously determined.     

Chiral cruciferous phytoalexins: preparation, absolute configuration, and biological activity

Synthesized by an efficient one-pot spirocyclization method, two chiral cruciferous phytoalexins, 1-methoxyspirobrassinin (2) and 1-methoxyspirobrassinol methyl ether (4a), were prepared through optical resolution using the chiral HPLC method of corresponding racemates. The absolute configuration of natural (+)-2 was elucidated as R by using the direct comparison of ECD and VCD spectra with those of known (S)-(-)-spirobrassinin (1). Another chiral phytoalexin, (-)-4a, had its absolute configuration 2R,3R elucidated through the comparison of observed and calculated VCD. Interestingly, the absolute configurations of natural (S)-(-)-spirobrassinin (1) and (R)-(+)-1-methoxyspirobrassinin (2) were opposite of each other, even though their structures are almost similar, with the exception of an N-methoxy group. A significant difference in the antiproliferative activity between (2R,3R)-(-) and (2S,3S)-(+)-4a was observed.     

Enantioresolution by the chiral phthalic acid method: absolute configurations of substituted benzylic alcohols

Substituted benzylic alcohols were enantioresolved by the chiral phthalic acid method as follows; 1) esterification of racemic alcohols with chiral phthalic acid, 2) separation of a diastereomeric mixture of the esters formed by HPLC on silica gel, and 3) recovery of enantiopure alcohols from the separated esters. The absolute configurations of chiral phthalic acid esters of benzylic alcohols were unambiguously determined by the X-ray crystallography using the campharsultam moiety as the internal standard of absolute configuration.     

Synthesis, chiral separation, and absolute configuration of bis-(N-aryl) atropisomeric triads: 1,2-bis-[4-methyl-2-(thi)oxo-2,3-dihydrothiazol-3-yl]-benzene

In this work, a series of 1,2-bis-[4-methyl-2-(thi)oxo-2,3-dihydrothiazol-3-yl]-benzene has been prepared. These atropisomeric molecular triads were exclusively found to exist in the anti-form. They were separated into enantiomers by liquid chromatography on a chiral support. The absolute configurations of the enantiomers were determined using a chemical correlation method together with chiral chromatography. The barriers to interconversion of the enantiomers were determined.     

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.     

Enantiodiscrimination of methamphetamine by circular dichroism using a porphyrin tweezer

Using exciton‐coupled circular dichroism (ECCD) spectroscopy, our lab was able to differentiate between the two enantiomers of methamphetamine using a commercially available porphyrin tweezer as an achiral host. The host–guest complex formed with (+)‐(S)‐methamphetamine produced a negative bisignate‐shaped ECCD spectrum, whereas the complex formed with (?)‐(R)‐methamphetamine produced a positive one. This sensitive technique could serve as an alternative method for the enantiodiscrimination of chiral methamphetamine, a commonly abused drug in the United States. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Stereochemical study of tolperisone, a muscle relaxant agent, by circular dichroism and ultraviolet spectroscopy

The stereochemistry of tolperisone, a chiral aryl-alkyl basic ketone was investigated by means of circular dichroism (CD) and ultraviolet (UV) spectroscopy. The unusually high optical activity of tolperisone hydrochloride in the n-->pi* region is interpreted by the presence of a chiral conformer in solution. For stereochemical reasons, the C = O group and the aromatic moiety lack coplanarity by forming an inherently dissymetric chromophore, of M helicity. Similar helicity prevails in the crystal phase, according to the solid-state CD spectrum of (-)-tolperisone HCl salt. The chirality rule proposed by Snatzke for nonplanar benzoyl chromophores predicts the absolute configuration of (-)-tolperisone hydrochloride to be R, in agreement with other alpha-methyl-beta-amino-ketones.     

Enantioresolution and absolute configurations of chiral meta-substituted diphenylmethanols as determined by X-ray crystallographic and 1H NMR anisotropy methods

meta-Substituted diphenylmethanols were enantioresolved by the method of chiral phthalic acid yielding enantiopure alcohols. Their absolute configurations were unambiguously determined by X-ray crystallography of chiral phthalate esters and/or by the (1)H NMR anisotropy method using 2-methoxy-2-(1-naphthyl)propionic acid.     

The enduring legacy of Koji Nakanishi's research on natural products and bioorganic chemistry. Part 2. Inception and establishment of the ECD exciton chirality method in 1960s to 1970s: A marvel of Nakanishi's Japanese team

The electronic circular dichroism (ECD) exciton chirality method is very useful for determining the absolute configuration (AC) of chiral compounds. In the ECD spectroscopy, the chromophore-chromophore interaction, ie, exciton coupling, is very important. For example, Harada and Nakanishi first discovered in 1969 that chiral dibenzoates exhibit exciton split bisignate Cotton effects, from the sign of which the screw sense between two long axes of benzoate chromophores, ie, the AC of dibenzoate, can be determined. This method was named the dibenzoate chirality rule and has been successfully applied to various natural products to determine their ACs. During these studies, it was also found that this CD method was expanded to encompass other aromatic and olefin chromophores like naphthalene, diene, enone, etc. Therefore, the name of the dibenzaote chirality rule was changed to the CD exciton chirality method. In 1970s, there were heated controversies about the inconsistency between X-ray Bijvoet and CD exciton chirality methods, which was a shocking and serious problem in the community of molecular chirality research. Harada and coworkers synthesized the most ideal cage compound with two anthracene chromophores to connect X-ray Bijvoet and CD exciton chitality methods and proved that these two methods are consistent with each other.     

Simple protocols for NMR analysis of the enantiomeric purity of chiral primary amines

A simple three-component chiral derivatization protocol for determining the enantiopurity of chiral primary amines by 1H NMR spectroscopic analysis is described here. The method involves condensation of the amines with 2-formylphenylboronic acid and enantiopure 1,1'-bi-2-naphthol. This approach affords a mixture of diastereoisomeric iminoboronate esters whose ratio can be determined by the integration of well-resolved diastereotopic resonances in their 1H NMR spectra, thus enabling the enantiopurity of the parent amine to be determined easily. The protocol, as described, takes less than 90 min to complete.     

The dirhodium-method in the determination of absolute configurations of phospholene chalcogenides

The 1H, 13C, and 31P NMR signals of six chiral phospholene chalcogenides (X = O, S, Se) are duplicated in the presence of one mole equivalent of the chiral auxiliary Rh2[(R)-MTPA]4 (diastereomeric dispersion Deltanu; in Hz). The samples were investigated as nonracemic mixtures of enantiomers with known absolute configurations so that signs can be attributed to the Deltanu-values and each signal set can be assigned to the respective enantiomer. The signs are uniform--in particular those of 1H nuclei--and nearly independent of the nature of the chalcogen atom. Thus, if the absolute configuration of one compound is known, it is possible to derive absolute configurations in the whole series (correlation method).