Chiral Organic Compounds Research Articles

Catalytic enantioselective synthesis of chiral organic compounds of ultra-high purity of >99% ee.

Shortly after the discovery of Zr-catalyzed carboalumination of alkynes in 1978, we sought expansion of the scope of this reaction so as to develop its alkene version for catalytic asymmetric C–C bond formation, namely the ZACA (Zr-catalyzed asymmetric carboalumination of alkenes). However, this seemingly easy task proved to be quite challenging. The ZACA reaction was finally discovered in 1995 by suppressing three competitive side reactions, i.e., (i) cyclic carbometalation, (ii) β-H transfer hydrometalation, and (iii) alkene polymerization. The ZACA reaction has been used to significantly modernize and improve syntheses of various natural products including deoxypolypropionates and isoprenoids. This review focuses on our recent progress on the development of ZACA–lipase-catalyzed acetylation–transition metal-catalyzed cross-coupling processes for highly efficient and enantioselective syntheses of a wide range of chiral organic compounds with ultra-high enantiomeric purities.

Enantiomer distribution of major chiral volatile organic compounds in selected types of herbal honeys.

In this article, volatile organic compounds in 14 honey samples (rosemary, eucalyptus, orange, thyme, sage, and lavender) were identified. Volatile organic compounds were extracted using a solid phase microextraction method followed by gas chromatography connected with mass spectrometry analysis. The studied honey samples were compared based on their volatile organic compounds composition. In total, more than 180 compounds were detected in the studied samples. The detected compounds belong to various chemical classes such as terpenes, alcohols, acids, aldehydes, ketones, esters, norisoprenoids, benzene and furane derivatives, and organic compounds containing sulfur and nitrogen heteroatom. Ten chiral compounds (linalool, trans-linalool oxide, cis-linalool oxide, 4-terpineol, α-terpineol, hotrienol, and four stereoisomers of lilac aldehydes) were selected for further chiral separation.

ChemInform Abstract: Porphyrin Tweezer Receptors: Binding Studies, Conformational Properties and Applications

AbstractReview: 65 refs.

The determination of botanical origin of honeys based on enantiomer distribution of chiral volatile organic compounds

The enantiomer ratios of chiral volatile organic compounds in rapeseed, chestnut, orange, acacia, sunflower and linden honeys were determined by multi-dimensional gas chromatography using solid phase microextraction (SPME) as a sample pre-treatment procedure. Linalool oxides, linalool and hotrienol were present at the highest concentration levels, while significantly lower amounts of α-terpineol, 4-terpineol and all isomers of lilac aldehydes were found in all studied samples. On the other hand, enantiomer distribution of some chiral organic compounds in honey depends on their botanical origin. The significant differences in enantiomer ratio of linalool were observed for rapeseed honey that allows us to distinguish this type of honey from the other ones. The enantiomer ratios of lilac aldehydes were useful for distinguishing of orange and acacia honey from other studied monofloral honeys. Similarly, different enantiomer ratio of 4-terpineol was found for sunflower honeys.

Cytochrome P450 Catalyzed Oxidative Hydroxylation of Achiral Organic Compounds with Simultaneous Creation of Two Chirality Centers in a Single CH Activation Step

AbstractRegio‐ and stereoselective oxidative hydroxylation of achiral or chiral organic compounds mediated by synthetic reagents, catalysts, or enzymes generally leads to the formation of one new chiral center that appears in the respective enantiomeric or diastereomeric alcohols. By contrast, when subjecting appropriate achiral compounds to this type of CH activation, the simultaneous creation of two chiral centers with a defined relative and absolute configuration may result, provided that control of the regio‐, diastereo‐, and enantioselectivity is ensured. The present study demonstrates that such control is possible by using wild type or mutant forms of the monooxygenase cytochrome P450 BM3 as catalysts in the oxidative hydroxylation of methylcyclohexane and seven other monosubstituted cyclohexane derivatives.

Cytochrome P450 Catalyzed Oxidative Hydroxylation of Achiral Organic Compounds with Simultaneous Creation of Two Chirality Centers in a Single CH Activation Step

Regio- and stereoselective oxidative hydroxylation of achiral or chiral organic compounds mediated by synthetic reagents, catalysts, or enzymes generally leads to the formation of one new chiral center that appears in the respective enantiomeric or diastereomeric alcohols. By contrast, when subjecting appropriate achiral compounds to this type of C-H activation, the simultaneous creation of two chiral centers with a defined relative and absolute configuration may result, provided that control of the regio-, diastereo-, and enantioselectivity is ensured. The present study demonstrates that such control is possible by using wild type or mutant forms of the monooxygenase cytochrome P450 BM3 as catalysts in the oxidative hydroxylation of methylcyclohexane and seven other monosubstituted cyclohexane derivatives.

Enantiomeric distribution of major chiral volatile organic compounds in juniper‐flavored distillates

The enantiomeric ratios of chiral volatile organic compounds in juniper-flavored spirits produced by various processing technologies in different EU countries were determined by multidimensional GC using solid-phase microextraction and liquid-liquid extraction as a sample pretreatment procedure. In total, more than 260 compounds were detected in studied spirits from which linalool, α-terpineol, 4-terpineol, linalool oxides, α-pinene, and verbenone were selected for enantiomeric separation. The significant differences in enantiomeric ratio of linalool and cis-linalool oxide allowed us to distinguish between samples produced in Slovakia and the United Kingdom from those produced in Germany, Czech Republic, and Belgium. The pure enantiomer of trans-linalool oxide was found only in samples from Germany. It was shown that the enantiomeric ratio is independent of the sample treatment procedure, and only small differences up to 1% were observed.

Compound‐specific stable carbon isotope analysis of galaxolide enantiomers in sediment using gas chromatography/isotope ratio monitoring mass spectrometry

Both chiral analysis and compound-specific stable carbon isotope analysis have limitations when applied to environmental research. However, the combination of these two techniques might overcome their respective limitation and give more insight into the enantioselective fate and source apportionment of chiral organic contaminants. After Soxhlet extraction and clean-up, sediment extracts were further pre-concentrated using normal-phase preparative high-performance liquid chromatography to isolate sufficient quantities of highly purified galaxolide (1,3,4,6,7,8-hexahydro-4,6,6,7,8,8-hexamethylcyclopenta(g)-2-benzopyran; HHCB). The enantiomeric fractions and stable carbon isotopes of the HHCB were determined using gas chromatography/mass spectrometry (GC/MS) and GC/isotope ratio mass spectrometry (IRMS). The method was validated by analysis of the enantiomeric fractions and the stable carbon isotope ratios of the HHCB standard at each step of the pre-concentration procedure, and no significant enantiomeric and isotopic fractionation was found. The sediment sample was further used to test the developed method, and it was shown that the HHCB enantiomers in the sediment sample exhibited significantly different δ(13) C values (-33.03 to -24.57‰) and a slight enantiomeric fractionation (0.507 and 0.490) from a HHCB standard reference compound (-26.50 to -26.21‰ for δ(13) C values, and 0.519 and 0.497 for enantiomeric fractions). This work offers a novel approach to elucidating the sources and the abiotic or biological transformation processes of HHCB in the environment and will offer a perspective for assessing the environment fate of any chiral organic compound.

Amino Acids and the Asymmetry of Life

‘How did life start on Earth?’ and ‘Why were left-handed amino acids selected for the architecture of proteins?’ A new attempt to answer these questions of high public and interdisciplinary scientific interest will be provided by this review. It will describe most recent experimental data on how the basic and molecular building blocks of life, amino acids, formed in a prebiotic setting. Most amino acids are chiral, that is that they cannot be superimposed with their mirror image molecules (enantiomers). In processes triggering the origin of life on Earth, the equal occurrence, i.e. the parity between left-handed amino acids and their right-handed mirror images, was violated. In the case of amino acids, the balance was tipped to the left – as a result of which life's proteins today exclusively implement the left-handed form of amino acids, called l-amino acid enantiomers. Neither plants, nor animals, including humans, make use of d-amino acids for the molecular architecture of their proteins (enzymes). This review addresses the molecular asymmetry of amino acids in living organisms, namely the preference for left-handedness. What was the cause for the violation of molecular parity of amino acids in the emergence of life on Earth? All the fascinating models proposed by physicists, chemists, and biologists will be vividly presented including the scientific conflicts. Special emphasis will be given to amino acid enantiomers that were subjected to chiral photons. The interaction between racemic molecules and chiral photons was shown to produce an enantiomeric enrichment that will be discussed in the context of absolute asymmetric synthesis. The concluding paragraphs will describe the attempt to verify any of those models with the chirality-module of the Rosetta mission. This European space mission contains probe Philae that was launched on board the Rosetta spacecraft with the aim of landing on the icy surface of comet 67P/Churyumov-Gerasimenko and analysing whether chiral organic compounds are present that could have been brought to the Earth by comet impacts.

Chiral Heteropoly Blues and Controllable Switching of Achiral Polyoxometalate Clusters

Managing the blues: Chiral heteropoly blues of achiral polyoxometalate clusters were created through an intermolecular interaction with a chiral organic compound. Controllable chiroptical switching of the cluster complexes was possible through reversible photochromism of the polyoxometalates (see picture).

ChemInform Abstract: Synthesis without Metals

AbstractReview: 174 refs.

ChemInform Abstract: Diastereoselective Organocatalytic Michael Addition of 2‐Arylacetates Having an Electron‐Withdrawing Group to Nitroalkenes.

AbstractAmong various chiral organic compounds tested, BFTU is found to be optimal for the process.

Aminocatalytic Asymmetric Diels–Alder Reactions via HOMO Activation

In the first successful catalytic asymmetric Diels-Alder reaction in 1979, Koga and colleagues used a chiral aluminum complex as a Lewis acid catalyst, but since then, researchers have developed numerous catalytic systems for these reactions. By 2000, several chiral organic compounds, such as the salts of imidazolidinones or TADDOLs, emerged as robust catalysts in the asymmetric Diels-Alder reactions. According to frontier molecular orbital theory, most of these catalysts employ a LUMO-lowering strategy as a means of activating electron-deficient dienophiles. Only rarely do chiral catalysts take advantage of the alternative strategy of activating the HOMO. In this Account we will discuss the development of asymmetric Diels-Alder reactions based on the HOMO-raising effects of chiral amines. First, we show that enamine intermediates formed in situ between an amine catalyst and enolizable aliphatic aldehydes can act as electron-rich dienophiles in inverse-electron-demand Diels-Alder reactions. We describe the preparation of a variety of oxygen- or nitrogen-containing heterocycles with high optical purity. Then, we demonstrate that the dienamine species from α,β-unsaturated aldehydes can act either as electron-rich dienes in normal-electron-demand Diels-Alder reactions or as dienophiles in inverse-electron-demand Diels-Alder reactions. These reactions generally occur with high chemo-, regio-, and stereoselectivity. Finally, we introduce a new activation mode for Diels-Alder reactions, in which reactive trienamine intermediates derived from 2,4-dienals or even 2,4-dienones play a key role. Notably, we observe remarkable β,ε-regioselectivity and obtain excellent stereocontrol even at the very remote ε-reactive center-up to seven bonds away from the chiral center of the amine catalyst. These results demonstrate that a HOMO-activation strategy via aminocatalysis could become a significant tool in asymmetric Diels-Alder reactions. In addition, these reactions using enamine, dienamine, or trienamine intermediates produce a diverse array of densely functionalized cyclic scaffolds, which may serve as valuable structures in drug discovery and natural product synthesis.

ChemInform Abstract: Selenoxide Elimination and [2,3]‐Sigmatropic Rearrangement

AbstractReview: 120 refs.

Enantioselective Fluorescent Sensors: A Tale of BINOL

The development of automated, high-throughput organic synthesis and screening techniques has created an urgent demand for methods that rapidly determine the enantiomeric composition of chiral compounds. Enantioselective fluorescent sensors offer the potential for real-time, high-sensitivity techniques for determining enantiomeric data in high-throughput chiral assays. In this Account, we describe a range of fluorescent sensors derived from 1,1'-bi-2-naphthol (BINOL), a readily available biaryl compound with axial chirality. We show that BINOL can be used to construct structurally diverse, chiral fluorescent sensors to carry out highly enantioselective, sensitive recognition of chiral amino alcohols, α-hydroxycarboxylic acids, and amino acid derivatives. For example, we prepared an (S)-BINOL derivative whose 3,3'-positions are attached to two chiral amino alcohol units, each having two phenyl substituents. This compound shows a fluorescence enhancement of 950-fold in the presence of (S)-mandelic acid but very little change in the presence of (R)-mandelic acid. It also allows the enantiomers of this α-hydroxycarboxylic acid to be visually discriminated by an enantioselective precipitation process. A structurally similar (S)-BINOL-amino alcohol molecule, but with three rather than two phenyl substitutents in each of the two amino alcohol units, was found to exhibit generally enantioselective fluorescence responses toward structurally diverse α-hydroxycarboxylic acids. We further prepared a pseudoenantiomeric analogue of this compound from (R)-H(8)BINOL, which has the opposite chiral configuration at both the biaryl center as well as the pendant amino alcohols. These two compounds have opposite enantioselectivity in the recognition of a chiral substrate, with distinctly different fluorescence emission wavelengths. By mixing them together, we developed a pseudoenantiomeric sensor pair to facilitate chiral assays. Using this pseudoenantiomeric sensor pair allows both the concentration and the enantiomeric composition of a substrate to be determined in a single fluorescence measurement. We synthesized another compound by ligating a terpyridine unit to BINOL and found that coordination of a Cu(II) ion to the terpyridine unit almost completely quenched its fluorescence. Displacement of the Cu(2+) ion from this complex by chiral amino alcohols leads to enantioselective fluorescence enhancement. This BINOL-terpyridine-Cu(II) complex also exhibits enantioselective gel collapsing in the presence of chiral amino alcohols, providing a new visual chiral discrimination method. When a series of light-absorbing conjugated units are attached to the BINOL structure, the resulting multiarmed dendritic molecules show greatly amplified fluorescence responses. Thus, the light harvesting effect of dendrimers can be used to greatly increase the sensitivity of the fluorescent sensors. The progress described here demonstrates that highly enantioselective and sensitive fluorescent sensors can be obtained through a systematic investigation of the structure-property relation between the sensors and the substrates. These sensors show great potential for the development of rapid assays of chiral organic compounds.

Chiral Imprinting with Amino Acids of Ordered Mesoporous Silica Exhibiting Enantioselectivity after Calcination

Chiral ordered mesoporous silica (COMS) was synthesized in basic media by combining tetraethyl orthosilicate and quaternized aminosilane (with a templating role) silica sources together with four different standard amino acids (arginine, histidine, isoleucine, and proline). Besides the hexagonal MCM-41-type structure, narrow pore size distribution, and high specific surface area, it was found that these solids have potential for enantiomeric separation because of the transference of chirality from the amino acid to the silica. This is illustrated by the resolution of several racemic mixtures (those of proline, isoleucine, trans-4-hydroxyproline, pipecolic acid, valine, leucine, and phenylglycine) with the calcined COMS prepared with l-proline. The opposite behavior observed in induced circular dichroism experiments with calcined COMS, obtained using both enantiomers of proline, confirmed their chiral nature. The high number and variety of existing amino acids, and chiral organic compounds in general, make...

Recent Advances in Catalytic Enantioselective Fluorination of Active Methines

Organofluorine compounds are central importance in the pharmaceutical and agrochemical industries because the replacement of a hydrogen with a fluorine atom in biologically active molecules can be beneficial in terms of physicochemical properties and biological activities. Thus, the development of effective methodologies for the preparation of chiral organic fluorine compounds through C-F bond formation is still a highly desirable goal in synthetic organic chemistry. In this account, we review latest progresses in the area of catalytic enantioselective electrophilic fluorination of active methine compounds.

Direct Racemic Mixture Synthesis of Fluorinated Amino Acids by Perfluoroalkyl Radical Addition to Dehydroamino Acids Terminated by Asymmetric Protonation

AbstractThe development of efficient methods for the synthesis and purification of chiral organic compounds is a challenge in modern science and technology. Pharmaceutically and agrochemically important compounds are especially required in optically pure form. We report the racemic mixture synthesis of β‐perfluoroalkyl α‐amino acids, which is based on the In‐mediated addition of perfluoroalkyl radicals to dehydroamino acids followed by asymmetric protonation. All the enantiomers can be separated by using a single chiral HPLC column, without orthogonal use of a fluorous column.

Preparation and Ferroelectric Properties of New Chiral Liquid Crystalline Organic Radical Compounds

We have synthesized new chiral liquid crystalline (LC) organic radical compounds 2 and 3, which are the derivatives of the previously reported compounds 1 containing a chiral cyclic nitroxide unit and an ester group in the mesogen core, and their ferroelectric properties have been studied. The enantiomerically enriched (2S,5S)-2 and (2S,5S)-3 showed an SmC * phase for which their ferroelectric properties such as spontaneous polarization (Ps) and tilt angle (θ) were compared with those of (2S,5S)-1.

Atmospheric Heterogeneous Stereochemistry

While many biogenic and anthropogenic organic constituents in the atmosphere are surface-active and chiral, the role of stereochemistry in heterogeneous oxidation chemistry in the atmosphere has not yet been evaluated. Here, we present nonlinear vibrational surface spectra of fused silica substrates functionalized with quinuclidine diastereomers during exposure to 10(11) to 10(13) molecules of ozone per cm(3) in 1 atm helium to model ozone-limited and ozone-rich tropospheric conditions. Kinetic studies show that diastereomers that orient their reactive C=C double bonds toward the gas phase exhibit heterogeneous ozonolysis rate constants that are 2 times faster than diastereomers that orient their C=C double bonds away from the gas phase. Insofar as our laboratory model studies are representative of real world environments, our studies suggest that the propensity of aerosol particles coated with chiral semivolatile organic compounds to react with ozone may depend on stereochemistry. We expect that the differences in chemical accessibility will lead to the enrichment of one oxidation product stereoisomer over the other. The oxidation products could be gaseous or surface-bound, indicating that kinetic resolution could lead to the stereochemical enrichment of the gas phase or the aerosol, which may have also been important in prebiotic chemistry. Implications of these results for chiral markers that would allow for source appointments of anthropogenic versus biogenic carbon emissions are discussed.