New bulky chiral Lewis acid catalyst: 3,3'-di(2-mesitylethynyl)binaphthol-titanium(IV) complex

A new chiral Lewis acid catalyst 9 was prepared in situ from a 1:2 molar mixture of (R)-3,3'-di(2-mesitylethynyl)binaphthol (6) and titanium(IV) isopropoxide at ambient temperature. The 3- and 3'-substituents on 6 were effective for preventing undesired aggregation between Ti(IV) complexes and increasing the enantioselectivity (up to 82% ee) in the Diels-Alder reaction of methacrolein with cyclopentadiene.     

Relative Stereochemistry and Absolute Configuration of Farinosin,a Eudesmanolide From Encelia farinosa

The naturally occurring eudesmanolide farinosin ( 1 ) is now fully characterized for the first time despite its original isolation almost half a century ago. The early assumed relative stereochemistry and absolute configuration were confirmed by vibrational circular dichroism together with evaluation of the Hooft X‐ray parameters. The molecular conformation is very similar in the gas stage and in the solid state. Chirality 28:415–419, 2016. © 2016 Wiley Periodicals, Inc.     

Exo-selective asymmetric Diels-Alder reaction of acrylate ester

Diels-Alder reaction of 2-acryloyloxy-2'-(2-pyridylazo)-1,1'-binaphthyl with cyclopentadiene in the presence of an equimolar amount of tin(IV) chloride showed unusual exo-selectivity with a high degree of diastereofacial differentiation.     

Absolute configuration assignment of (+)‐fluralaner using vibrational circular dichroism

The absolute configurations of the separated enantiomers of fluralaner, a racemic animal health product used to prevent fleas and ticks, have been assigned using vibrational circular dichroism (VCD). The crystallographic structure of the active enantiomer (+)‐fluralaner has previously been shown to have the (S ) configuration using small molecule crystallography. We sought a faster analytical method to determine the absolute configuration of the separated enantiomers. When comparing the measured IR (infrared) and VCD spectra, it is apparent that the amide carbonyl groups appear in the IR but are nearly absent in the VCD. Computational work to calculate the VCD and IR using in vacuo models, implicit solvation, and explicitly solvated complexes has implicated conformational averaging of the carbonyl VCD intensities.     

Study on the Absolute Configurations of 3‐Alkylphthalides using TDDFT Calculations of Chiroptical Properties

Absolute configurations (ACs) of 3‐alkylphthalides including natural products (?)‐3‐n‐butylphthalide ( (S)‐1 ) and fuscinarin have been studied using chiroptical properties and quantum chemical calculation. Electronic circular dichroism and optical rotatory dispersion spectra of (S)‐1 predicted adopting time‐dependent density functional theory and hybrid functionals coincide very well with the experimental and literature data of (S)‐1 , leading unambiguously to AC assignment as S for levorotatory isomer. The relationship between structures and chiroptical properties of 3‐alkylphthalides were also studied using theoretical calculation. It is found that when the alkyl group is adjacent to the single chiral center in the molecule, both the length of the alkyl side chain and the polarity of solvent may exert significant effect on electronic circular dichroism spectra. On the basis of these observations, it is recommended that the long‐chain alkyl group may be replaced by at least propyl instead of methyl group in such compounds. The present work shows that combination of chiroptical properties and ab initio calculations can provide a feasible and reliable way to the AC establishment of novel 3‐alkylphthalide derivatives with a high degree of confidence. Chirality 24:987‐993, 2012. © 2012 Wiley Periodicals, Inc.     

Circular dichroism spectroscopy and DFT calculations in determining absolute configuration and E/Z isomers of conjugated oximes

The primary purpose of this work was to demonstrate the suitability of circular dichroism (CD) spectroscopy in stereochemical studies of α,β ‐unsaturated oximes, with particular emphasis on determination of E and Z geometry of the oxime double bond. As models for this study, O‐phenyl and O‐triphenylmethyl (trityl) oximes of 4‐hydroxy‐2‐methylcyclopent‐2‐en‐1‐one were selected. These model compounds differ in both absolute configuration at C4 carbon atom and E ‐Z configuration of the oxime double bond. The basic dichroic technique applied was electronic circular dichroism (ECD) assisted by quantum‐chemical calculations and vibrational circular dichroism (VCD) for selected cases. Such an approach enabled effective implementation of both goals. Thus, we were able to associate the signs of Cotton effects in the range of 190–240 nm with the absolute configuration at C4 and within 240–300 nm with the E ‐ or Z ‐geometry of the oxime double bond. Within this work, optical activity of the protecting trityl group was also studied towards formation of the propeller‐shaped conformations by using the same combined CD/DFT methodology. As shown, the helical structure of the trityl group has a considerable influence on the ECD spectra. However, the MPM and PMP conformers of the trityl group are in fact almost equally populated in the conformational equilibrium, making it impossible to distinguish them. On the other hand, rotamers of the hydroxyl group at C4 show a decisive impact on the VCD spectra in both phenoxy and trityl oximes.     

Absolute Configuration Determination and Convenient Asymmetric Synthesis of cis-3-(9-Anthryl)cyclohexanol with Proline as a Catalyst

cis‐(3R)‐(9‐anthryl) derivative of cyclohexanol was conveniently obtained in enantiomerically pure form from 2‐cyclohexenone using asymmetric Michael addition of anthrone catalyzed by l ‐proline in a key step. The absolute configuration of the addition product was unequivocally determined by means of electronic circular dichroism measurements combined with calculation of the circular dichroism spectrum by using a density functional theory method. Chirality 24:833–839, 2012. © 2012 Wiley Periodicals, Inc.     

Absolute configuration of phomactatriene diterpenoids obtained by Wagner‐Meerwein rearrangement of epimeric verticillols

The epimeric diterpenes (+)‐(1S,3E,7E,11S,12S)‐verticilla‐3,7‐dien‐12‐ol ( 1 ), isolated from Bursera suntui, and (+)‐(1S,3E,7E,11S,12R)‐verticilla‐3,7‐dien‐12‐ol ( 2 ), isolated from Bursera kerberi, gave the same Wagner‐Meerwein rearrangement product (?)‐(1E,4Z,8Z,11S,12R)‐phomacta‐1,(15)4,8‐triene ( 3 ). The Et₂O:BF₃‐induced transformations evidence that verticillenes and phomactanes, both containing the bicyclo[9.3.1]pentadecane skeleton, are biogenetically related through the verticillen‐12‐yl cation ( A ⁺ ), which also is a key intermediate in the biosynthetic pathways to generate antitumor taxanes. Molecular modeling using the Monte Carlo protocol, followed by density functional theory (DFT) geometry optimization employing the hybrid functionals B3LYP and B3PW91, both with the DGDZVP basis set, secured the configuration of 3 as followed from the good agreement between the calculated and experimental vibrational circular dichroism spectra. Similar DFT calculations allowed determining the absolute configuration of (+)‐(1R,4R,5R,8S,9S,11S,12R,15R)‐1,15:4,5:8,9‐triepoxyphomactane ( 9 ), which surprisingly derives from epoxidation of the second minimum energy conformer of 3 .     

Absolute Configuration Determination of Azulenyl Diols Isolated From Asymmetric Pinacol Coupling

A convenient enantioselective approach for the pinacol coupling of 1‐acetylazulene involving easily accessible (R)‐ or (S)‐BINOLs as chiral additive is reported. This supposes the preformation of the chiral titanium–BINOL complex in 1:2 ratio and subsequent reduction with zinc when, 2,3‐di(azulen‐1‐yl)butane‐2,3‐diol can be isolated in around 60% enantiomeric excess. The absolute configuration of the isolated enantiomers was assigned by comparison of the experimental and Boltzmann‐weighted calculated VCD and ECD spectra and assigned as (+)‐(2S;3S)‐di(azulen‐1‐yl)butane‐2,3‐diol. Chirality 27:826–834, 2015. © 2015 Wiley Periodicals, Inc.     

Absolute configuration of the ocimene monoterpenoids from Artemisia absinthium

The absolute configuration (AC) of the naturally occurring ocimenes (−)‐(3S ,5Z )‐2,6‐dimethyl‐2,3‐epoxyocta‐5,7‐diene ( 1 ) and (−)‐(3S ,5Z )‐2,6‐dimethylocta‐5,7‐dien‐2,3‐diol ( 2 ), isolated from the essential oils of domesticated specimens of Artemisia absinthium , followed by vibrational circular dichroism (VCD) studies of 1 , as well as from the acetonide 3 and the monoacetate 4 , both derived from 2 , since secondary alcohols are not the best functional groups to be present during VCD studies in solution due to intermolecular associations. The AC follows from comparison of experimental and calculated VCD spectra that were obtained by Density Functional Theory computation at the B3LYP/DGDZVP level of theory. Careful nuclear magnetic resonance (NMR) measurements were compared with literature values, providing for the first time systematic ¹H and ¹³C chemical shift data. Regarding homonuclear ¹H coupling constants, after performing a few irradiation experiments that showed the presence of several small long‐range interactions, the complete set of coupling constants for 3 , which is representative of the four studied molecules, was determined by iterations using the PERCH software. This procedure even allowed assigning the pro ‐R and pro ‐S methyl group signals of the two gem ‐dimethyl groups present in 3 .     

Absolute configuration and conformational analysis of a degradation product of inhalation anesthetic Sevoflurane: A vibrational circular dichroism study

1,1,1,3,3-pentafluoro-2-(fluoromethoxy)-3-methoxypropane, compound B, is a product obtained in the degradation of the anesthetic Sevoflurane. Enantiopure (+)-B was investigated using vibrational circular dichroism (VCD). Experimental absorption and VCD spectra of (+)-B in CDCl(3) solution in the 2,000-900 cm(-1) region are compared with the ab initio predictions of absorption and VCD spectra obtained from density functional theory using B3LYP/6-31G* basis set for different conformers of (S)-1,1,1,3,3-pentafluoro-2-(fluoromethoxy)-3-methoxypropane. This comparison indicates that (+)-B is of the (S)-configuration in CDCl(3) solution, in agreement with previous literature results. Our results also indicate that this compound adopts six predominant conformations in CDCl(3) solution.     

Synthesis and stereochemical characterization of optically active 1,2-diarylethane-1,2-diols: useful chiral controllers in the Ti-mediated enantioselective sulfoxidation

The series of phenylsubstituted 1,2-diphenylethane-1,2-diols 2a-h was prepared in high chemical (70--80%) and optical yields (approximately 90%) by Sharpless syn-dihydroxylation of the corresponding (E)-1,2-diarylethenes, in turn obtained by McMurry or Wittig reactions. The enantiomeric excesses of the samples were determined by HPLC analysis using Chiralcel OD chiral stationary phase (CSP). This CSP was able to resolve all the diols, except for 2g, with alpha values ranging between 1.10--1.64. In all cases the (R,R) antipode was eluted first. (R,R) absolute configuration was assigned to the dextrorotatory (CHCl(3)) diols 2a--h by analyzing the CD spectra of their 2,2-dimethyl-1,3-dioxolanes 3a--h. In fact, the CD spectra of all these dioxolanes present a positive couplet (210--180 nm range) which can be nonempirically related to an (R,R) absolute configuration of the two stereocenters.     

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.     

Reducing Molecular Flexibility by Cyclization for Elucidation of Absolute Configuration by CD Calculations: Daurichromenic Acid

Circular dichroism (CD) calculations of flexible natural products have been difficult because of the large number of low‐energy conformers and ambiguous Boltzmann distributions. In this article, through electronic (ECD) and vibrational (VCD) studies on a natural product, (+)‐daurichromenic acid, we demonstrate that derivatization of a flexible molecule can dramatically reduce its flexibility. This work also shows the usefulness of derivatization for diminishing computational expenses required for optimization and CD calculations, and for increasing the reliability of the assignment of absolute configuration. Chirality 28:453–459, 2016. © 2016 Wiley Periodicals, Inc.     

Conformational investigation of two isomeric chiral porphyrins: a convergent approach with different techniques

The conformation in solution of two atropisomeric meso-tetrabinaphthyl porphyrins, used as catalytic precursors in asymmetric synthesis, was studied by means of experimental ((1)H-NMR ROESY, UV-Vis, and circular dichroism) and computational (semiempirical structure optimization, DeVoe's coupled oscillators calculations) methods. UV-Vis and CD spectra are calculated for several molecular models, with a systematic sampling of the conformational space, and compared to the experimental ones, leading to a structural hypothesis which is confirmed by NMR and PM3.     

Enantioselective sequential transformations by use of metal complexes: Tandem-Knoevenagel-hetero-Diels–Alder reactions with new chiral Lewis acids

Enantioselective reaction of the aldehydes 1a-g and the 1,3-dicarbonyl compound 2 in the presence of the chiral Lewis acid 5 , derived from diacetone glucose, leads in a sequential transformation consisting of a Knoevenagel condensation and an intramolecular Diels Alder reaction to the cycloadducts 4a-g with an ee value up to 88%. The selectivity is strongly dependent upon the temperature and solvent giving best results at room temperature in isodurene; in agreement with the principle of isoinversion, the ee values decrease at lower and higher temperatures. © 1993 Wiley-Liss, Inc.     

Absolute Configurations of Four Resorcylic Acid Lactones,Paecilomycins J − M,by CD/TDDFT Calculations

The absolute configurations of four resorcylic acid lactones (RALs), paecilomycins J ? M ( 1 ? 3 and 5 ), were assigned by Time‐Dependent Density‐Functional Theory (TDDFT) calculations of their electronic circular dichroism (CD) spectra. The previously reported structure 4 for paecilomycin M was found to be incorrect and should be changed to structure 5 . Analysis of structure‐spectrum relationship for this group of RALs suggested that V′‐shape conformations give type I CD spectra (two negative Cotton effects around 300 and 260 nm, a positive Cotton effect around 220 nm) while V‐shape conformations yield type II spectra (signs of three Cotton effects were opposite to those in type I). Chirality 26:44–50, 2013. © 2013 Wiley Periodicals, Inc.     

Absolute Configuration and Predominant Conformations of a Chiral Crown Ether‐Based Colorimetric Sensor: A Vibrational Circular Dichroism Spectroscopy and DFT Study of Chiral Recognition

In the present work, we report a comprehensive vibrational circular dichroism (VCD) spectroscopic study of a chiral crown ether which features an axial chiral 3.3'‐diphenyl‐1,1'‐binaphthyl group as chiral moiety. By comparing the experimental and calculated VCD spectra, we show that the presumably very flexible crown ether preferably adopts only one ring conformation. Conformational flexibility is observed in the 2,4‐dinitrophenyl‐diazophenol group, which was previously introduced for colorimetric detection of primary amines and amino alcohols (Cho et al., Chirality 2011;23:349–353). The VCD spectra of the host–guest complexes with phenyl glycinol (PG) and phenyl alaninol have been studied as well. Based on the spectra calculated, it is shown that the diastereomeric complexes in general can be differentiated using VCD spectroscopy. Furthermore, the experimental VCD spectra of the complexes of the host molecule with PG support the above finding. Chirality 25:294–300, 2013. © 2013 Wiley Periodicals, Inc.     

Formation and temperature stability of G-quadruplex structures studied by electronic and vibrational circular dichroism spectroscopy combined with ab initio calculations

Variations in the structure of d(GGGA)(5) oligonucleotide in the presence of Li(+), Na(+), and K(+) ions and its temperature stability were studied using electronic and vibrational circular dichroism, IR absorption, and ab initio calculations with the Becke 3-Lee-Yang-Parr functional at the 6-31G** level. The samples were characterized by nondenaturing gel electrophoresis. Oligonucleotide d(GGGA)(5) in the presence of Li(+) forms a nonplanar single tetramer, with angles of 102 degrees and 171 degrees between neighboring guanine bases. This tetramer changes its geometry at temperatures >50 degrees C, but does not form a quadruplex structure. In the presence of Na(+), the d(GGGA)(5) structure was optimized to almost planar tetramers with an angle of 177 degrees between neighboring guanines. The spectral results suggest that it stacks into a quadruplex helical structure. This quadruplex structure decayed to a single tetramer at temperatures >60 degrees C. The Hartree-Fock energies imply that d(GGGA)(5) prefers to form complexes with Na(+) rather than Li(+). The d(GGGA)(5) structure in the presence of monovalent ions is stabilized against thermal denaturation in the order Li(+) < Na(+) < K(+).     

Tetranuclear titanium 7,7'-modified binaphtholate cluster as a novel chiral Lewis acid catalyst

Chiral tetranuclear Ti cluster, a cubic structure constituted of four Ti atoms and OHs, and six (R)-binaphthols (BINOL) bridged two Ti atoms as ligands, is shown to be a novel chiral Lewis acid catalyst for the [2+3] cycloaddition reaction with nitrones. The chiral Ti clusters with 7,7'-substituted (R)-BINOL ligands was synthesized to give enhanced enantiomeric excesses up to 78% ee.