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1169 KiB

Open AccessArticle

Acid Catalyzed Alcoholysis of Sulfinamides: Unusual Stereochemistry, Kinetics and a Question of Mechanism Involving Sulfurane Intermediates and Their Pseudorotation

by Bogdan Bujnicki, Józef Drabowicz and Marian Mikołajczyk

Molecules 2015, 20(2), 2949-2972; https://doi.org/10.3390/molecules20022949 - 11 Feb 2015

Cited by 11 | Viewed by 8906

Abstract

The synthesis of optically active sulfinic acid esters has been accomplished by the acid catalyzed alcoholysis of optically active sulfinamides. Sulfinates are formed in this reaction with a full or predominant inversion of configuration at chiral sulfur or with predominant retention of configuration. [...] Read more.

The synthesis of optically active sulfinic acid esters has been accomplished by the acid catalyzed alcoholysis of optically active sulfinamides. Sulfinates are formed in this reaction with a full or predominant inversion of configuration at chiral sulfur or with predominant retention of configuration. The steric course of the reaction depends mainly on the size of the dialkylamido group in the sulfinamides and of the alcohols used as nucleophilic reagents. It has been found that bulky reaction components preferentially form sulfinates with retention of configuration. It has been demonstrated that the stereochemical outcome of the reaction can be changed from inversion to retention and vice versa by adding inorganic salts to the acidic reaction medium. The unusual stereochemistry of this typical bimolecular nucleophilic substitution reaction, as confirmed by kinetic measurements, has been rationalized in terms of the addition-elimination mechanism, A-E, involving sulfuranes as intermediates which undergo pseudorotations. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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874 KiB

Open AccessArticle

Comparison of the Separation Performances of Cinchona Alkaloid-Based Zwitterionic Stationary Phases in the Enantioseparation of β²- and β³-Amino Acids

by István Ilisz, Nóra Grecsó, Aleksandra Misicka, Dagmara Tymecka, László Lázár, Wolfgang Lindner and Antal Péter

Molecules 2015, 20(1), 70-87; https://doi.org/10.3390/molecules20010070 - 23 Dec 2014

Cited by 20 | Viewed by 6660

Abstract

The enantiomers of twelve unusual β²- and β³-homoamino acids containing the same side-chains were separated on chiral stationary phases containing a quinine- or quinidine-based zwitterionic ion-exchanger as chiral selector. The effects of the mobile phase composition, the nature and [...] Read more.

The enantiomers of twelve unusual β²- and β³-homoamino acids containing the same side-chains were separated on chiral stationary phases containing a quinine- or quinidine-based zwitterionic ion-exchanger as chiral selector. The effects of the mobile phase composition, the nature and concentration of the acid and base additives and temperature on the separations were investigated. The changes in standard enthalpy, ∆(∆H°), entropy, ∆(∆S°), and free energy, ∆(∆G°), were calculated from the linear van’t Hoff plots derived from the ln α vs. 1/T curves in the studied temperature range (10–50 °C). The values of the thermodynamic parameters depended on the nature of the selectors, the structures of the analytes, and the positions of the substituents on the analytes. A comparison of the zwitterionic stationary phases revealed that the quinidine-based ZWIX(−)™ column exhibited much better selectivity for both β²- and β³-amino acids than the quinine-based ZWIX(+)™ column, and the separation performances of both the ZWIX(+)™ and ZWIX(−)™ columns were better for β²-amino acids. The elution sequence was determined in some cases and was observed to be R < S and S < R on the ZWIX(+)™ and ZWIX(−)™ columns, respectively. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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782 KiB

Open AccessArticle

Liquid Chromatographic Resolution of Fendiline and Its Analogues on a Chiral Stationary Phase Based on (+)-(18-Crown-6)-2,3,11,12-tetracarboxylic Acid

by Ga Ram Lee and Myung Ho Hyun

Molecules 2014, 19(12), 21386-21397; https://doi.org/10.3390/molecules191221386 - 19 Dec 2014

Cited by 9 | Viewed by 6849

Abstract

Fendiline, an effective anti-anginal drug for the treatment of coronary heart diseases, and its sixteen analogues were resolved on a CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. Fendiline was resolved quite well with the separation factor (α) of 1.25 and resolution (R_S) of [...] Read more.

Fendiline, an effective anti-anginal drug for the treatment of coronary heart diseases, and its sixteen analogues were resolved on a CSP based on (+)-(18-crown-6)-2,3,11,12-tetracarboxylic acid. Fendiline was resolved quite well with the separation factor (α) of 1.25 and resolution (R_S) of 1.55 when a mobile phase consisting of methanol–acetonitrile–trifluoroacetic acid–triethylamine at a ratio of 80/20/0.1/0.5 (v/v/v/v) was used. The comparison of the chromatographic behaviors for the resolution of fendiline and its analogues indicated that the 3,3-diphenylpropyl group bonded to the secondary amino group of fendiline is important in the chiral recognition and the difference in the steric bulkiness between the phenyl group and the methyl group at the chiral center of fendiline is also important in the chiral recognition. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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606 KiB

Open AccessArticle

Homoconjugation vs. Exciton Coupling in Chiral α,β-Unsaturated Bicyclo[3.3.1]nonane Dinitrile and Carboxylic Acids

by Gintautas Bagdžiūnas, Eugenijus Butkus and Sigitas Stončius

Molecules 2014, 19(7), 9893-9906; https://doi.org/10.3390/molecules19079893 - 8 Jul 2014

Cited by 4 | Viewed by 7097

Abstract

The chiroptical properties of enantiomerically pure bicyclo[3.3.1]nona-2,6-diene-2,6-dicarbonitrile and related acids were studied by circular dichroism spectroscopy and theoretical computations. A consideration of the molecular structure of the synthesized difunctional compounds revealed that chromophores are predisposed to transannular through-space interaction due to a favourable [...] Read more.

The chiroptical properties of enantiomerically pure bicyclo[3.3.1]nona-2,6-diene-2,6-dicarbonitrile and related acids were studied by circular dichroism spectroscopy and theoretical computations. A consideration of the molecular structure of the synthesized difunctional compounds revealed that chromophores are predisposed to transannular through-space interaction due to a favourable conformation of the bicyclic skeleton and a rather small interchromophoric distance. Evidence for non-exciton-type coupling between the two acrylonitrile and acrylate moieties in 3 and 4, respectively, was obtained by chiroptical spectroscopy and DFT calculations. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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299 KiB

Open AccessArticle

Ni-Catalyzed Homoallylation of Polyhydroxy N,O-Acetals with Conjugated Dienes Promoted by Triethylborane

by Takamichi Mori, Yusuke Akioka, Gen Onodera and Masanari Kimura

Molecules 2014, 19(7), 9288-9306; https://doi.org/10.3390/molecules19079288 - 2 Jul 2014

Cited by 7 | Viewed by 5834

Abstract

In the presence of Ni-catalyst and triethylborane, N,O-acetals prepared from glycolaldehyde and glyceraldehyde with primary amines in situ underwent homoallylation with conjugated dienes to provide 2-amino-5-hexenols in high regio- and stereoselectivity. Under similar reaction conditions, N,O-acetals from [...] Read more.

In the presence of Ni-catalyst and triethylborane, N,O-acetals prepared from glycolaldehyde and glyceraldehyde with primary amines in situ underwent homoallylation with conjugated dienes to provide 2-amino-5-hexenols in high regio- and stereoselectivity. Under similar reaction conditions, N,O-acetals from carbohydrates with primary amines provided the corresponding polyhydroxy-bishomoallylamines in good to reasonable yields. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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818 KiB

Open AccessArticle

Chiroptical Properties and the Racemization of Pyrene and Tetrathiafulvalene-Substituted Allene: Substitution and Solvent Effects on Racemization in Tetrathiafulvalenylallene

by Masashi Hasegawa, Seiya Iwata, Yasuto Sone, Junta Endo, Hideyo Matsuzawa and Yasuhiro Mazaki

Molecules 2014, 19(3), 2829-2841; https://doi.org/10.3390/molecules19032829 - 4 Mar 2014

Cited by 8 | Viewed by 8495

Abstract

Dissymmetric 1,3-diphenylallene derivative 3 connected with 4,5-bis(methyl-thio)tetrathiafulvalenyl and 1-pyrenyl substituents was prepared and characterized. The molecular structure was determined by X-ray crystallographic analysis. Optical resolution was accomplished using a recycling chiral HPLC, and its chiroptical properties were examined with optical rotation and electronic [...] Read more.

Dissymmetric 1,3-diphenylallene derivative 3 connected with 4,5-bis(methyl-thio)tetrathiafulvalenyl and 1-pyrenyl substituents was prepared and characterized. The molecular structure was determined by X-ray crystallographic analysis. Optical resolution was accomplished using a recycling chiral HPLC, and its chiroptical properties were examined with optical rotation and electronic circular dichroism (ECD) spectra. The title compound underwent photoracemization under daylight. This behavior was investigated in various solvents and compared with that of 1,3-bis(tetrathiafulvalenyl)allene (bis-TTF-allene) derivative 2. The first-order rate plot of the intensity of the ECD spectra at a given time interval gave the rate of racemization. Mild racemization was observed in polar solvents, whereas a relatively fast rate was obtained in less polar solvents. In addition, the TTF groups of the allene also accelerate the racemization rate. These results suggest that the racemization mechanism occurs via a non-polar diradical structure. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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1261 KiB

Open AccessArticle

Influence of Temperature on the Enantioselectivity of Koga Tetraamines on Amylose Chiral Stationary Phases

by Hong-Xun Guo, Steven Wu and Jingshun Sun

Molecules 2014, 19(1), 9-21; https://doi.org/10.3390/molecules19010009 - 19 Dec 2013

Cited by 8 | Viewed by 6474

Abstract

Enantioseparation is largely based on the formation of transitional complexes, the solvation species, the stationary phase configurations or the diastereomeric complexes formed by analytes and the chiral stationary phase. Temperature and the chemical nature and composition of the eluent play significant roles during [...] Read more.

Enantioseparation is largely based on the formation of transitional complexes, the solvation species, the stationary phase configurations or the diastereomeric complexes formed by analytes and the chiral stationary phase. Temperature and the chemical nature and composition of the eluent play significant roles during that process. In this study; unique temperature-induced behaviors were observed during the enantioseparation of Koga tetraamines, also known as Koga bases, on polysaccharide chiral stationary phases, in which van’t Hoff plots were acquired over a temperature range of 10 °C to 40 °C with 5 °C increments. Koga bases were eluted by a mixture of methanol and 2-propanol with 0.03% triethylamine as a modifier. The van’t Hoff plots are linear in the case of eluent containing equal volumes of methanol and 2-propanol. Increasing 2-propanol concentration from 50% to 85% in volume led to non-linear van’t Hoff plots over the entire temperature range studied. Examination of the individual non-linear plots revealed two linear regions of 10 °C–20 °C and 20 °C–40 °C. Transition from one linear region to the other at 20 °C indicates alterations of chiral stationary phase conformation and/or enantioseparation mechanism as a result of temperature changes. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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465 KiB

Open AccessArticle

Examination of the Potential for Adaptive Chirality of the Nitrogen Chiral Center in Aza-Aspartame

by Samir H. Bouayad-Gervais and William D. Lubell

Molecules 2013, 18(12), 14739-14746; https://doi.org/10.3390/molecules181214739 - 28 Nov 2013

Cited by 17 | Viewed by 12731

Abstract

The potential for dynamic chirality of an azapeptide nitrogen was examined by substitution of nitrogen for the α-carbon of the aspartate residue in the sweetener S,S-aspartame. Considering that S,S- and R,S-aspartame possess sweet and [...] Read more.

The potential for dynamic chirality of an azapeptide nitrogen was examined by substitution of nitrogen for the α-carbon of the aspartate residue in the sweetener S,S-aspartame. Considering that S,S- and R,S-aspartame possess sweet and bitter tastes, respectively, a bitter-sweet taste of aza-aspartame 9 could be indicative of a low isomerization barrier for nitrogen chirality inter-conversion. Aza-aspartame 9 was synthesized by a combination of hydrazine and peptide chemistry. Crystallization of 9 indicated a R,S-configuration in the solid state; however, the aza-residue chiral center was considerably flattened relative to its natural amino acid counterpart. On tasting, the authors considered aza-aspartame 9 to be slightly bitter or tasteless. The lack of bitter sweet taste of aza-aspartame 9 may be due to flattening from sp² hybridization in the urea as well as a high barrier for sp³ nitrogen inter-conversion, both of which may interfere with recognition by taste receptors. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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393 KiB

Open AccessArticle

Perfluoroalkanesulfonamide Organocatalysts for Asymmetric Conjugate Additions of Branched Aldehydes to Vinyl Sulfones

by Kosuke Nakashima, Miho Murahashi, Hiroki Yuasa, Mariko Ina, Norihiro Tada, Akichika Itoh, Shin-ichi Hirashima, Yuji Koseki and Tsuyoshi Miura

Molecules 2013, 18(12), 14529-14542; https://doi.org/10.3390/molecules181214529 - 25 Nov 2013

Cited by 11 | Viewed by 6507

Abstract

Asymmetric conjugate additions of branched aldehydes to vinyl sulfones promoted by sulfonamide organocatalyst 6 or 7 have been developed, allowing facile synthesis of the corresponding adducts with all-carbon quaternary stereocenters in excellent yields with up to 95% ee. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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1560 KiB

Open AccessArticle

Deracemization of Axially Chiral Nicotinamides by Dynamic Salt Formation with Enantiopure Dibenzoyltartaric Acid (DBTA)

by Fumitoshi Yagishita, Norifumi Kamataki, Kazuma Okamoto, Shota Kanno, Takashi Mino, Hyuma Masu and Masami Sakamoto

Molecules 2013, 18(11), 14430-14447; https://doi.org/10.3390/molecules181114430 - 21 Nov 2013

Cited by 7 | Viewed by 7466

Abstract

Dynamic atroposelective resolution of chiral salts derived from oily racemic nicotinamides and enantiopure dibenzoyltartaric acid (DBTA) was achieved by crystallization. The absolute structures of the axial chiral nicotinamides were determined by X-ray structural analysis. The chirality could be controlled by the selection of [...] Read more.

Dynamic atroposelective resolution of chiral salts derived from oily racemic nicotinamides and enantiopure dibenzoyltartaric acid (DBTA) was achieved by crystallization. The absolute structures of the axial chiral nicotinamides were determined by X-ray structural analysis. The chirality could be controlled by the selection of enantiopure DBTA as a chiral auxiliary. The axial chirality generated by dynamic salt formation was retained for a long period after dissolving the chiral salt in solution even after removal of the chiral acid. The rate of racemization of nicotinamides could be controlled based on the temperature and solvent properties, and that of the salts was prolonged compared to free nicotinamides, as the molecular structure of the pyridinium ion in the salts was different from that of acid-free nicotinamides. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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899 KiB

Open AccessArticle

Conformational Analysis of Geometric Isomers of Pitavastatin Together with Their Lactonized Analogues

by Damjan Makuc, Jan Fabris, Zdenko Časar and Janez Plavec

Molecules 2013, 18(11), 13283-13296; https://doi.org/10.3390/molecules181113283 - 28 Oct 2013

Cited by 5 | Viewed by 7799

Abstract

Super-statins are synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which is the rate-limiting enzyme responsible for the biosynthesis of cholesterol. All of the super-statins with a C=C double bond spacer between the heterocyclic and the dihydroxycarboxylic moiety that are currently on the market exist [...] Read more.

Super-statins are synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, which is the rate-limiting enzyme responsible for the biosynthesis of cholesterol. All of the super-statins with a C=C double bond spacer between the heterocyclic and the dihydroxycarboxylic moiety that are currently on the market exist as E-isomers. To extend the understanding of conformational and thermodynamic preferences of Z-isomeric super-statin analogues, this study focused on analyzing pitavastatin and its lactonized derivatives via NMR spectroscopy and ab initio calculations. Z-isomeric pitavastatin analogues exist in solution as a pair of interconverting rotamers, where the Gibbs free energies between the major and minor rotamers are within 0.12 and 0.25 kcal mol⁻¹ and the rotational energy barriers are between 15.0 and 15.9 kcal mol⁻¹. The analysis of long-range coupling constants and ab initio calculations revealed that rotation across the C5'–C7 single bond is essential for generating a pair of atropisomers. The overall comparison of the results between Z-isomeric pitavastatin and rosuvastatin analogues demonstrated that the former are to some extent more flexible to attain numerous conformations. Demonstrating how structural differences between super-statin analogues induce distinctive conformational preferences provides important insight into the super-statins’ conformational variability and may well improve future drug design. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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970 KiB

Open AccessArticle

Characterization of Amide Bond Conformers for a Novel Heterocyclic Template of N-acylhydrazone Derivatives

by Alexandra Basilio Lopes, Eduardo Miguez, Arthur Eugen Kümmerle, Victor Marcos Rumjanek, Carlos Alberto Manssour Fraga and Eliezer J. Barreiro

Molecules 2013, 18(10), 11683-11704; https://doi.org/10.3390/molecules181011683 - 25 Sep 2013

Cited by 90 | Viewed by 10459

Abstract

Herein we describe NMR experiments and structural modifications of 4-methyl-2-phenylpyrimidine-N-acylhydrazone compounds (aryl-NAH) in order to discover if duplication of some signals in their ¹H- and ¹³C-NMR spectra was related to a mixture of imine double bond stereoisomers (E/Z [...] Read more.

Herein we describe NMR experiments and structural modifications of 4-methyl-2-phenylpyrimidine-N-acylhydrazone compounds (aryl-NAH) in order to discover if duplication of some signals in their ¹H- and ¹³C-NMR spectra was related to a mixture of imine double bond stereoisomers (E/Z) or CO-NH bond conformers (syn and anti-periplanar). NMR data from NOEdiff, 2D-NOESY and ¹H-NMR spectra at different temperatures, and also the synthesis of isopropylidene hydrazone revealed the nature of duplicated signals of a 4-methyl-2-phenylpyrimidine-N-acylhydrazone derivative as a mixture of two conformers in solution. Further we investigated the stereoelectronic influence of substituents at the ortho position on the pyrimidine ring with respect to the carbonyl group, as well as the electronic effects of pyrimidine by changing it to phenyl. The conformer equilibrium was attributed to the decoplanarization of the aromatic ring and carbonyl group (generated by an ortho-alkyl group) and/or the electron withdrawing character of the pyrimidine ring. Both effects increased the rotational barrier of the C-N amide bond, as verified by the DG^≠ values calculated from dynamic NMR. As far as we know, it is the first description of aryl-NAH compounds presenting two CO-NH bond- related conformations. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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Review

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423 KiB

Open AccessReview

Stereocontrolled Synthesis and Functionalization of Cyclobutanes and Cyclobutanones

by Francesco Secci, Angelo Frongia and Pier Paolo Piras

Molecules 2013, 18(12), 15541-15572; https://doi.org/10.3390/molecules181215541 - 13 Dec 2013

Cited by 89 | Viewed by 12696

Abstract

In the last decade a certain number of new cyclobutane and cyclobutanone synthesis and functionalization protocols have been published. Organo- and biocatalyzed eco-friendly approaches to cyclobutane-containing molecules have been developed with interesting results. Also, successful new total synthesis of bioactive compounds and drugs [...] Read more.

In the last decade a certain number of new cyclobutane and cyclobutanone synthesis and functionalization protocols have been published. Organo- and biocatalyzed eco-friendly approaches to cyclobutane-containing molecules have been developed with interesting results. Also, successful new total synthesis of bioactive compounds and drugs have been recently reported where a four membered ring represented the key intermediate. Therefore, the rising interest in this field represents a great point of discussion for the scientific community, disclosing the synthetic potential of strained four membered ring carbocyclic compounds. Herein we report a critical survey on the literature concerning the enantiocontrolled synthesis and functionalization of cyclobutane derivatives, with particular attention to metal-free, low impact methodologies, published during the period 2000–2013. Full article

(This article belongs to the Special Issue Dynamic Stereochemistry)

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