Achiral‐to‐Chiral Transition in Benzil Solidification: Analogies with Racemic Conglomerates Systems Showing Deracemization

Experimental results show that benzil (1,2‐diphenyl‐1,2‐ethanedione), an achiral compound that crystallizes as a racemic conglomerate, yields by solidification polycrystalline scalemic mixtures of high enantiomeric excesses. These results are related to those previously reported in this type of compounds on deracemizations of racemic mixtures of crystal enantiomorphs obtained by wet grinding. However, the present results strongly suggest that these experiments cannot be explained without taking into account chiral recognition interactions at the level of precritical clusters. The conditions that would define a general thermodynamic scenario for such deracemizations are discussed. Chirality 25:393–399, 2013. © 2013 Wiley Periodicals, Inc.     

Chiroptical Properties of Carbo[6]Helicene Derivatives Bearing Extended π‐Conjugated Cyano Substituents

New carbo[6]helicene derivatives grafted with π‐conjugated cyano‐phenyl arms were synthesized in enantiopure forms and their π‐conjugation examined by UV–vis spectroscopy. The influence of the π‐conjugation on the circular dichroism spectra and molar rotations is discussed based on comparing experimental data with results from quantum‐chemical calculations. The results highlight the fact that increasing the spatial extension of the π‐system in a helicene molecule is an efficient way of increasing its molar rotation. Chirality 25:455–465, 2013. © 2013 Wiley Periodicals, Inc.     

Axially chiral N‐(o‐aryl)‐4‐hydroxy‐2‐oxazolidinone derivatives from diastereoselective reduction of N‐(o‐aryl)‐2,4‐oxazolidinediones: Thermally interconvertible atropisomers via ring‐chain‐ring tautomerization

The reduction of the axially chiral N‐(o‐aryl)‐5,5‐dimethyl‐2,4‐oxazolidinediones by NaBH₄ yielded axially chiral N‐(o‐aryl)‐4‐hydroxy‐5,5‐dimethyl‐2‐oxazolidinone enantiomers having a chiral center at C‐4, with 100% diastereoselectivity as has been shown by their ¹H and ¹³C NMR spectra and by enantioselective HPLC analysis. The resolved enantiomeric isomers were found to interconvert thermally through an aldehyde intermediate formed upon ring cleavage via a latent ring‐chain‐ring tautomerization. It was found that the rate of enantiomerization depended on the size and the electronic effect of the ortho substituent present on the aryl ring bonded to the nitrogen of the heterocycle. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Circularly polarized luminescence of helically assembled pyrene π‐stacks on RNA and DNA duplexes

In this report, we describe the circularly polarized luminescence (CPL) of the RNA duplexes having one to four 2′‐O‐pyrene modified uridines ( Upy ) and the DNA duplexes having two, four, and six pyrene modified non‐nucleosidic linkers ( Py ). Both the pyrene π‐stack arrays formed on the RNA and DNA double helical structures exhibited pyrene excimer fluorescence. In the pyrene‐modified RNA systems, the RNA duplex having four Upy s gives CPL emission with g_lum value of <0.01 at 480 nm. The structure of pyrene stacks on the RNA duplex may be rigidly regulated with increase in the Upy domains, which resulted in the CPL emission. In the DNA systems, the pyrene‐modified duplexes containing two and four Pys exhibited CPL emission with g_lum values of <0.001 at 505 nm. The pyrene π‐stack arrays presented here show CPL emission. However, the g_lum values are relatively small when compared with our previous system consisting of the pyrene‐zipper arrays on RNA.     

Enantiomeric 4‐Acylamino‐6‐alkyloxy‐2 Alkylthiopyrimidines As Potential A3 Adenosine Receptor Antagonists: HPLC Chiral Resolution and Absolute Configuration Assignment by a Full Set of Chiroptical Spectroscopy

The chiral separation of enantiomeric couples of three potential A₃ adenosine receptor antagonists: (R/S)‐N‐(6‐(1‐phenylethoxy)‐2‐(propylthio)pyrimidin‐4‐yl)acetamide ( 1 ), (R/S)‐N‐(2‐(1‐phenylethylthio)‐6‐propoxypyrimidin‐4‐yl)acetamide ( 2 ), and (R/S)‐N‐(2‐(benzylthio)‐6‐sec‐butoxypyrimidin‐4‐yl)acetamide ( 3 ) was achieved by high‐performance liquid chromatography (HPLC). Three types of chiroptical spectroscopies, namely, optical rotatory dispersion (ORD), electronic circular dichroism (ECD), and vibrational circular dichroism (VCD), were applied to enantiomeric compounds. Through comparison with Density Functional Theory (DFT) calculations, encompassing extensive conformational analysis, full assignment of the absolute configuration (AC) for the three sets of compounds was obtained. Chirality 28:434–440, 2016. © 2016 Wiley Periodicals, Inc.     

VCD study of α‐methylbenzyl amine derivatives: Detection of the unchanged chiral motif

Chiral α‐methylbenzyl amine is a well known and often used chiral auxiliary, e.g., in the resolution of racemates or asymmetric catalysis. In this work, α‐methylbenzyl amine and its derivatives N,α‐dimethylbenzyl amine, N,N,α‐trimethylbenzyl amine, and bis[α‐methylbenzyl] amine were investigated by vibrational circular dichroism (VCD) spectroscopy and density functional theory (DFT). For all compounds, stable low energy conformers were obtained by the DFT calculations and based on those, the theoretical vibrational absorption (VA) and VCD spectra were calculated and compared with experimental spectra. Hence, the absolute configurations and conformational preferences were determined. A qualitative comparison of all the experimental VCD spectra of the investigated chiral molecules supported by the calculated ones is given which clearly shows similarities between the spectra of the different chiral amines. These can be assigned to vibrations of the unchanged chiral center. Chirality 2010. © 2010 Wiley‐Liss, Inc.     

Not as easy as π: An insertional residue does not explain the π‐helix gain‐of‐function in two‐component FMN reductases

The π‐helix located at the tetramer interface of two‐component FMN‐dependent reductases contributes to the structural divergence from canonical FMN‐bound reductases within the NADPH:FMN reductase family. The π‐helix in the SsuE FMN‐dependent reductase of the alkanesulfonate monooxygenase system has been proposed to be generated by the insertion of a Tyr residue in the conserved α4‐helix. Variants of Tyr118 were generated, and their X‐ray crystal structures determined, to evaluate how these alterations affect the structural integrity of the π‐helix. The structure of the Y118A SsuE π‐helix was converted to an α‐helix, similar to the FMN‐bound members of the NADPH:FMN reductase family. Although the π‐helix was altered, the FMN binding region remained unchanged. Conversely, deletion of Tyr118 disrupted the secondary structural properties of the π‐helix, generating a random coil region in the middle of helix 4. Both the Y118A and Δ118 SsuE SsuE variants crystallize as a dimer. The MsuE FMN reductase involved in the desulfonation of methanesulfonates is structurally similar to SsuE, but the π‐helix contains a His insertional residue. Exchanging the π‐helix insertional residue of each enzyme did not result in equivalent kinetic properties. Structure‐based sequence analysis further demonstrated the presence of a similar Tyr residue in an FMN‐bound reductase in the NADPH:FMN reductase family that is not sufficient to generate a π‐helix. Results from the structural and functional studies of the FMN‐dependent reductases suggest that the insertional residue alone is not solely responsible for generating the π‐helix, and additional structural adaptions occur to provide the altered gain of function.     

Determination of the Enantiomerization Barrier of the Residual Enantiomers of C3‐Symmetric Tris[3‐(1‐Methyl‐2‐Alkyl)Indolyl]Phosphane Oxides: Case Study of a Multitasking HPLC Investigation Based on an Immobilized Polysaccharide Stationary Phase

The residual enantiomers of three tris‐(3‐indolyl)‐phosphane oxides bearing different alkyl groups (methyl, ethyl or i‐propyl) in position 2 of the indole rings constituting the blades were separated on the immobilized type Chiralpak IC column in polar organic and reversed‐phase modes. The good enantioselectivity and versatility of the IC CSP allowed easy isolation of the enantiomerically highly enriched samples suitable for configurational stability studies. The enantiomerization barriers of residual phosphane oxides were evaluated both by off‐column techniques (CD signal and enantiomeric purity decay kinetics) and by dynamic enantioselective high‐performance liquid chromatography (HPLC). Chirality 27:888–899, 2015. © 2015 Wiley Periodicals, Inc.     

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.     

Toward a general mixed quantum/classical method for the calculation of the vibronic ECD of a flexible dye molecule with different stable conformers: Revisiting the case of 2,2,2‐trifluoro‐anthrylethanol

We extend a recently proposed mixed quantum/classical method for computing the vibronic electronic circular dichroism (ECD) spectrum of molecules with different conformers, to cases where more than one hindered rotation is present. The method generalizes the standard procedure, based on the simple Boltzmann average of the vibronic spectra of the stable conformers, and includes the contribution of structures that sample all the accessible conformational space. It is applied to the simulation of the ECD spectrum of (S)‐2,2,2‐trifluoroanthrylethanol, a molecule with easily interconvertible conformers, whose spectrum exhibits a pattern of alternating positive and negative vibronic peaks. Results are in very good agreement with experiment and show that spectra averaged over all the sampled conformational space can deviate significantly from the simple average of the contributions of the stable conformers. The present mixed quantum/classical method is able to capture the effect of the nonlinear dependence of the rotatory strength on the molecular structure and of the anharmonic couplings among the modes responsible for molecular flexibility. Despite its computational cost, the procedure is still affordable and promises to be useful in all cases where the ECD shape arises from a subtle balance between vibronic effects and conformational variety.     

Probing the interaction of distamycin A with S100β: the “unexpected” ability of S100β to bind to DNA‐binding ligands

DNA‐minor‐groove‐binding ligands are potent antineoplastic molecules. The antibiotic distamycin A is the prototype of one class of these DNA‐interfering molecules that have been largely used in vitro. The affinity of distamycin A for DNA is well known, and the structural details of the complexes with some B‐DNA and G‐quadruplex‐forming DNA sequences have been already elucidated. Here, we show that distamycin A binds S100β, a protein involved in the regulation of several cellular processes. The reported affinity of distamycin A for the calcium(II)‐loaded S100β reinforces the idea that some biological activities of the DNA‐minor‐groove‐binding ligands arise from the binding to cellular proteins. Copyright © 2015 John Wiley & Sons, Ltd.     

Binding Pockets and Pathways for Dioxygen through the KijD3 N‐Oxygenase in Complex with Flavin Mononucleotide Cofactor and a 3‐Aminoglucose Substrate: Predictions from Molecular Dynamics Simulations

In this work, two protein systems, Kij3D? FMN? AKM? O₂ and Kij3D? FMN? O₂, made of KijD3 N‐oxygenase, flavin mononucleotide (FMN) cofactor, dTDP‐3‐amino‐2,3,6‐trideoxy‐4‐keto‐3‐methyl‐D ‐glucose (AKM) substrate, and dioxygen (O₂), have been assembled by adding a molecule of O₂, and removing (or not) AKM, to crystal data for the Kij3D? FMN? AKM complex. Egress of AKM and O₂ from these systems was then investigated by applying a tiny external random force, in turn, to their center of mass in the course of molecular dynamics in explicit H₂O. It turned out that the wide AKM channel, even when emptied, does not constitute the main route for O₂ egress. Other routes appear to be also viable, while various binding pockets (BPs) outside the active center are prone to trap O₂. By reversing the reasoning, these can also be considered as routes for uptake of O₂ by the protein, before or after AKM uptake, while BPs may serve as reservoirs of O₂. This shows that the small molecule O₂ is capable of permeating the protein by exploiting all nearby interstices that are created on thermal fluctuations of the protein, rather than having necessarily to look for farther, permanent channels.