A Holistic Approach to Determining Stereochemistry of Potential Pharmaceuticals by Circular Dichroism with ß-Lactams as Test Cases.

This paper's main objective is to show that many different factors must be considered when solving stereochemical problems to avoid misleading conclusions and obtain conclusive results from the analysis of spectroscopic properties. Particularly in determining the absolute configuration, the use of chiroptical methods is crucial, especially when other techniques, including X-ray crystallography, fail, are not applicable, or give inconclusive results. Based on various ß-lactam derivatives as models, we show how to reliably determine their absolute configuration (AC) and preferred conformation from circular dichroism (CD) spectra. Comprehensive CD analysis, employing both approaches, i.e., traditional with their sector and helicity rules, and state-of-the-art supported by quantum chemistry (QC) calculations along with solvation models for both electronic (ECD) and vibrational (VCD) circular dichroism ranges, allows confident defining stereochemistry of the ß-lactams studied. Based on an in-depth analysis of the results, we have shown that choosing a proper chiroptical method/s strictly depends on the specific case and certain structural features.

A Critical Appraisal of Dimolybdenum Tetraacetate Application in Stereochemical Studies of vic-Diols by Circular Dichroism.

This critical appraisal is intended for users of the dimolybdenum method, well-established in electronic circular dichroism (ECD) to determine the absolute configuration of vic-diols and, in particular, for experimental researchers not being experts in chiroptical methods. The main goal is to demonstrate how to avoid misleading and ambiguous conclusions resulting from the rigorous application of the helicity rule by limiting the analysis to the vic-diol unit alone. We particularly focused on multichromophoric systems, especially those that may interfere with the absorption of an in situ formed dimolybdenum tetraacetate-diol complex. In this context, examples are presented of vic-diols for which stereochemical assignment based solely on the helicity rule is ambiguous and does not necessarily lead to correct results. The motivation for choosing these examples was to demonstrate the impact of the structure of the substrate on the complexation process with the metal core and its selectivity. For each selected case, results obtained are analyzed in detail together with a discussion of existing restrictions and choice of a support method to increase the credibility of the conclusion. Based on seven both educational and challenging examples, it was shown that the dimolybdenum methodology can also be effectively applied to complex chromophoric systems, provided that other chiroptical methods and/or computational support verify obtained results.

Research into the oxidation of abietic acid-derived enone with atmospheric oxygen.

This work presents results of methyl 7-oxoabiet-13(14)-en-18-oate (3) self-oxidation with air-oxygen in the presence of various bases such as triethylamine or sodium t-butoxide. While under aerobic conditions, the use of sodium t-butoxide as a base results in the formation of four isomeric alcohols, an addition of triethylamine into reaction medium directs the enone 3 oxidation to hydroperoxides. To clarify this base dependence and to obtain more in-depth information about this reaction additional studies with cyclohexenone as a reference enone have been undertaken. Their results demonstrated the predisposition of abietane hydroperoxides to oxidize α,ß-unsaturated ketones to epoxides in the presence of t-butoxide while reducing the hydroperoxide group to hydroxyl. This ability of hydroperoxides to epoxidize conjugated double bonds and confirmed by the present study intermolecular course allowed proposing a plausible mechanism for this reaction.

In Depth Analysis of Chiroptical Properties of Enones Derived from Abietic Acid.

With the use of inexpensive commercially available abietic acid, a whole series of abietane enones were prepared in high yields. The structures of all the products obtained were determined by comprehensive spectroscopic analysis with particular emphasis on the use of advanced NMR techniques, comparison with previously reported data and, where possible, by single crystal X-ray diffraction. However, in cases where X-ray crystallography was not applicable or compounds tested were unstable, a final stereochemical assignment could be inferred only by electronic circular dichroism (ECD) supported by vibrational circular dichroism to increase credibility. To reveal the relationship between structure and chiroptical properties, we used combined experimental and theoretical analysis of geometries, structural parameters, and chiroptical properties of all enones synthesized. A thorough analysis of their conformational flexibility by examining the effect of solvent and temperature on the ECD spectra was also used to achieve desired objectives. As a result, the impact of substituents adjacent to the enone chromophore on the conformation was determined by demonstrating that even slight changes in the position of hydroxyl and isopropyl groups attached to carbon C13 may substantially affect ECD curves' pattern, leading in some cases to Cotton effects sign reversal.

Solvation of 2-(hydroxymethyl)-2,5,7,8-tetramethyl-chroman-6-ol revealed by circular dichroism: a case of chromane helicity rule breaking.

The primary goal of this work is to clarify why 2-(hydroxymethyl)-2,5,7,8-tetramethyl-chroman-6-ol {(S)-TMChM} deviates from the chromane helicity rule under solvent change. The rule, applicable to determining the absolute configuration of molecules containing the chromane chromophore, binds the sign of the 1Lb Cotton effect (CE) with the helicity of the dihydropyran ring. In case of TMChM, however, this CE exhibits extreme solvent dependence: it is negative in non-coordinating solvents and positive in coordinating ones, irrespective of the helicity of the heterocyclic ring. TD-DFT calculations using PCM and hybrid solvation models were performed to explain origin of this phenomenon. It turned out that the 1Lb CE sign directly depends on the position of the phenolic OH group at carbon atom C6 (OHC6). In the absence of interactions with solvents (as in CCl4 or nC6H14) or when a solvent plays proton donor role (as in CHCl3), the OHC6 lies in the phenyl plane and the 1Lb CE sign follows the P/M helicity rule. In contrast, in proton acceptor solvents, like DMSO, CH3OH or CH3CN, the OHC6 group is deflected from the phenyl plane, and the 1Lb CE sign of individual (S)-TMChM conformers depends on the sector in which the OHC6 is located. Thus, in solution, the 1Lb CE sign is an average over different orientations of the OHC6 group and can be positive (as in DMSO and CH3OH) or negative (as in CH3CN) which means that it does not follow the chromane helicity rule. The impact of OHC6 on the 1Lb CE sign and thus the conclusions for the stereochemistry of chromans are demonstrated here for the first time. Additionally, a comparison of experimental and simulated ECD spectra, supported by VCD data, allowed to determine the geometry of intermolecular clusters formed in different solvents.

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,ß-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.

Chirality sensing of bioactive compounds with amino alcohol unit via circular dichroism.

The aim of the present work was to test various chiroptical techniques, including in particular the in situ dirhodium methodology, to assign the absolute configuration of 1,2- and 1,3-amino alcohols. As models, we selected mainly compounds that have both an additional strongly absorbing and interfering chromophoric system and application in medicinal chemistry. Determination of the absolute configuration (AC) of the tested molecules such as cinchona alkaloids, Tamiflu, and others was carried out using a combination of electronic and vibrational circular dichroism (ECD, VCD) spectroscopy. It has been demonstrated that both 1,2- and 1,3-aminol moieties are subject to the same sector rule correlating stereostructure of formed Rh2 -complex with chiroptical properties, and that the changes in the position of the stereogenic center do not affect its proper use.

Synthesis and Comprehensive Structural and Chiroptical Characterization of Enones Derived from (-)-α-Santonin by Experiment and Theory.

The aim of the present work is to explain the causes of the observed deviations from sector and helicity rules to determine the absolute configuration of optically active α,ß-unsaturated ketones by means of electronic circular dichroism (ECD). To this end, a series of model compounds with a common decahydronaphthalene skeleton representing both cisoid and transoid enones were synthesized. In the framework of this work, detailed dichroic studies supported by single crystal X-ray analysis were performed where possible. To assist the achievement of the desired objectives the conformational flexibility of the selected cis-enones through the dependence of solvent and temperature on the ECD spectra were examined. All experimental studies were supplemented by detailed DFT calculations. A notable result of the study is assessing the applicability of the enone sector and helicity rules in dichroic studies and potential restrictions. To this end, a number of factors that could determine the signs of the individual Cotton effects has been considered. Among these nonminimum structure effects, i.e., twisting of the enone chromophore and nonplanarity of the enone double bond can be mentioned.

Amine-catalyzed direct aldol reactions of hydroxy- and dihydroxyacetone: biomimetic synthesis of carbohydrates.

This article presents comprehensive studies on the application of primary, secondary, and tertiary amines as efficient organocatalysts for the de novo synthesis of ketoses and deoxyketoses. Mimicking the actions of aldolase enzymes, the synthesis of selected carbohydrates was accomplished in aqueous media by using proline- and serine-based organocatalysts. The presented methodology also provides direct access to unnatural L-carbohydrates from the (S)-glyceraldehyde precursor. Determination of the absolute configuration of all obtained sugars was feasible using a methodology consisting of concerted ECD and VCD spectroscopy.

Chromane helicity rule--scope and challenges based on an ECD study of various trolox derivatives.

The validity of the chromane helicity rule correlating the sense of twist within the dihydropyran ring with the CD sign of the (1)Lb band observed at ca. 290 nm in their electronic circular dichroism (ECD) spectra is examined using a set of natural (S)-trolox derivatives. To investigate both the scope and the limitations of the rule a combination of ECD spectroscopy, especially the temperature dependence of the ECD spectra, single crystal X-ray diffraction analyses, and density functional theory (DFT) calculations was used. A thorough conformational analysis supported by the X-ray data led to the identification of predominant conformers. Then, a comparison of the experimental ECD spectra with the spectra simulated by TDDFT calculations allowed for a reasonable interpretation of the accumulated data. The results clearly indicated that to avoid the possibility of erroneous conclusions the chromane helicity rule should be used with great caution. This is likely related to the conformational flexibility of tested compounds by which conformers of different helicities can be produced. Therefore, based on the results presented here, it is strongly recommended that the conclusions derived from analysis of experimental data are supported with the appropriate theoretical computations.

Chemoenzymatic approach to optically active 4-hydroxy-5-alkylcyclopent-2-en-1-one derivatives: an application of a combined circular dichroism spectroscopy and DFT calculations to assignment of absolute configuration.

A series of representative optically active derivatives of 4-hydroxy-5-alkylcyclopent-2-en-1-one were prepared from the respective 2-furyl methyl carbinols via the Piancatelli rearrangement followed by the enzymatic kinetic resolution of racemates. Applicability of chiroptical methods (experimental and calculated electronic circular dichroism [ECD] and vibrational circular dichroism [VCD] spectra) to determine the absolute configuration of both stereogenic centers in 4-hydroxy-5-methylcyclopent-2-en-1-one was demonstrated. It was also demonstrated that the concurrent application of ECD and VCD spectroscopy can be used for the determination of the configuration of two stereogenic centers.

Comprehensive chiroptical study of proline-containing diamide compounds.

The continuously growing interest in the understanding of peptide folding led to the conformational investigation of methylamides of N-acetyl-amino acids as diamide models. Here we report the results of detailed conformational analysis on Ac-Pro-NHMe and Ac-ß-HPro-NHMe diamides. These compounds were analyzed by experimental and computational methods, the conformational distributions obtained by Density Functional Theory (DFT) calculations for isolated and solvated diamide compounds are discussed. The conformational preference of proline-containing diamide compounds as a function of the ambience was observed by a number of chiroptical spectroscopic techniques, such as vibrational circular dichroism (VCD), electronic circular dichroism (ECD), Raman optical activity (ROA) spectroscopy, and additionally by single crystal X-ray diffraction analyses. Based on a comparison between Ac-Pro-NHMe and Ac-ß-HPro-NHMe, one can conclude that due to the greater conformational freedom of the ß-HPro derivative, Ac-ß-HPro-NHMe shows different behavior in solid- and solution-phase, as well. Ac-ß-HPro-NHMe tends to form cis Ac-ß-HPro amide conformation in water, dichloromethane, and acetonitrile in contrast to its α-Pro analog. On the other hand, the crystal structure of the ß-HPro compound cannot be related to any of the conformers obtained in vacuum and solution while the X-ray structure of Ac-Pro-NHMe was identified as tα(L)-, which is a trans Ac-Pro amide containing conformer also predominant in polar solvents.

Synthesis of a sucrose dimer with enone tether; a study on its functionalization.

The reaction of appropriately functionalized sucrose phosphonate with sucrose aldehyde afforded a dimer composed of two sucrose units connected via their C6-positions ('the glucose ends'). The carbonyl group in this product (enone) was stereoselectively reduced with zinc borohydride and the double bond (after protection of the allylic alcohol formed after reduction) was oxidized with osmium tetroxide to a diol. Absolute configurations of the allylic alcohol as well as the diol were determined by circular dichroism (CD) spectroscopy using the in situ dimolybdenum methodology.

Dimolybdenum tetracarboxylates as auxiliary chromophores in chiroptical studies of vic-diols.

The aim of the present work was to check the suitability of dimolybdenum carboxylates, other than commonly used [Mo2(OAc)4], as auxiliary chromophores for determining the absolute configuration of optically active vic-diols by means of electronic circular dichroism (ECD). To this end, a set of dimolybdenum tetracarboxylates was synthesized, and subsequently, the two most promising compounds were selected, namely dimolybdenum tetrakis(µ-pivalate) and tetrakis(µ-isovalerate). The selection was based on their solubility in commonly used solvents, their stability in solution, their tolerance to air exposure, as well as their utility for dichroic studies. The stability of the obtained in situ chiral complexes was verified by measuring the dependence of ECD, UV-vis, and NMR spectra on time, temperature, and concentration. We have shown that the ECD spectra of diverse vic-diols with these complexes are suitable for configurational assignment based on the correlation between signs of Cotton effects (CEs) arising in the spectra and the stereostructure of the ligand. Furthermore, to aid in the interpretation of experimental results, a separate set of DFT calculations has been incorporated to provide additional insight into the structure of the chiral complexes involved. In contrast to the earlier assumptions, experiments showed that the chelating mode of ligation is preferred for the studied complexes.

Enantioselective Extraction System Containing Binary Chiral Selectors and Chromatographic Enantioseparation Method for Determination of the Absolute Configuration of Enantiomers of Cyclopentolate.

The distribution coefficients and enantioseparation of cyclopentolate were studied in an extraction system containing d-tartaric acid ditertbutyl ester in organic phase and 2-hydroxypropyl-ß-cyclodextrin (HP-ß-CD) in aqueous phase. Various parameters involved in the enantioseparation such as the type and the concentration of chiral selectors, pH value and a wide range of organic solvents were investigated. The maximum enantioselectivity (α = 2.13) and optimum distribution coefficients (KR = 0.85, KS = 0.40) were obtained under the following conditions: 0.10 mol/L HP-ß-CD in aqueous phase and 0.20 mol/L d-tartaric acid ditertbutyl ester in decanol as organic phase. Cyclopentolate is present as a racemic mixture to the aqueous phase. The potentially different biological activities of cyclopentolate enantiomers have not been examined yet. Two chiral liquid chromatography methods have been developed for the direct separation of the enantiomers of cyclopentolate. First method was used for the quantification analysis of cyclopentolate enantiomers in aqueous phase. Second method used two chiroptical detectors: electronic circular dichroism (ECD) and optical rotation (OR) for the identification of individual cyclopentolate enantiomers from the organic phase enriched with (R)-enantiomer. The absolute stereochemistry was determined by means of the comparison of the experimental and computed ECD spectra and signs of OR. The ECD spectra of chiral analytes were measured on-line using HPLC-ECD technique.

Photoinduced isomerization of 23-oxosapogenins: conformational analysis and spectroscopic characterization of 22-isosapogenins.

The first synthesis of 22-isospirostane derivatives is described. They were obtained by photochemical isomerization of 23-oxosapogenins. The structure of 23-oxo-22-isotigogenin acetate (12) was proved by a single crystal X-ray diffraction, while structures of 23-oxo-22-isodiosgenin acetate (13) and 23-oxo-22-isosarsasapogenin acetate (14) were elucidated by spectroscopic methods. 22-Isodiosgenin acetate (17) was obtained by NaBH(4) reduction of the 23-oxo derivative 13 followed by the two-step Barton-McCombie deoxygenation procedure. Conformational analysis of 22-iso compounds was carried out with CD and NMR, as well as DFT calculations.

Ring-expanded bicyclic ß-lactams: a structure-chiroptical properties relationship investigation by experiment and calculations.

In the present work, the validity of the helicity rule relating the absolute configuration of the bridgehead carbon atom in bicyclic ß-lactams to the sign of the 220 nm band observed in their electronic circular dichroism (ECD) spectra is examined for ring-expanded cephalosporin analogues. To this end, a series of model compounds with a seven-membered ring condensed with the ß-lactam unit was synthesized. A key step of their synthesis was either the ring-closing metathesis (RCM) or the free radical cyclization leading to the seven-membered ring with an S, O, or C atom at the 6 position in the bicyclic skeleton. To investigate the scope and limitations of the simple, empirically established helicity rule, a combination of ECD spectroscopy, variable-temperature ECD measurements, X-ray analysis, and time-dependent density functional theory (TD-DFT) calculations was used. A comparison of the experimental ECD spectra with the spectra simulated by TD-DFT calculations gives a reasonable interpretation of the Cotton effects observed in the 240-215 nm spectral range. The results suggest that the helicity rule does not apply to the investigated compounds because of the planarity of their amide chromophore. Thus, these compounds do not constitute an exception to the rule that was established for bi- and polycyclic ß-lactams with the nonplanar amide chromophore only.

Structure-chiroptical properties relationship of carbapenams by experiment and theory.

The present work examines the relationship between the molecular structure and chiroptical properties of carbapenams through use of electronic circular dichroism spectroscopy (ECD). The applicability of the helicity rule that correlates the molecular structures of various ß-lactam analogues and their ECD spectra is examined against a set of differently substituted carbapenams. It is demonstrated that the studied compounds conform to the rule. The rule can be also applied to the carbapenams with an additional chromophoric unit interfering with the amide chromophore. For the representative carbapenams, the experimental curves are compared to the ECD spectra computed using time-dependent density functional theory (TDDFT) in order to validate the experimental data. The study reveals a high effectiveness of the ECD spectroscopy for the configurational assignment at the bridgehead carbon atom and demonstrates a strong dependence of the molecular conformation on substitution of the five-membered ring and side-chain flexibility of investigated carbapenams.

New insight into chiroptical properties of 1,2-diols cyclic sulfites.

The present work examines the relationship between the structure and chiroptical properties of cyclic sulfites utilizing the electronic circular dichroism (CD) and time-dependent density functional theory (TD-DFT). For some of the model compounds the study was additionally supported by the X-ray diffraction analysis. A comparison of the experimental and simulated CD spectra gave a reasonable interpretation of the Cotton effects observed in the 200-220 nm spectral range. The study revealed a high sensitivity of the CD spectra with regard to the configuration at the sulfur atom as well as the conformation of the ring bearing the sulfite chromophore. The results demonstrated that such a combined treatment enabled the determination of absolute configuration with a high degree of confidence.

Chiral base-catalyzed enantioselective synthesis of 4-aryloxyazetidinones and 3,4-benzo-5-oxacephams.

Readily available 4-formyloxyazetidinone was enantioselectively transformed into 3,4-benzo-2-hydroxy-5-oxacephams and 4-phenyloxyazetidinones upon treatment with 0.1 equiv of the cinchona alkaloid in toluene via intermolecular nucleophilic trapping of N-acyliminium intermediate by the hydroxyl moiety of phenols or o-hydroxybenzaldehydes. Additionally, the absolute configuration of title compounds was established by CD spectroscopy.