Synthesis and in vitro sodium channel blocking activity evaluation of novel homochiral mexiletine analogs

New chiral mexiletine analogs were synthesized in their optically active forms and evaluated in vitro as use‐dependent blockers of skeletal muscle sodium channels. Tests carried out on sodium currents of single muscle fibers of Rana esculenta demonstrated that all of them exerted a higher use‐dependent block than mexiletine. The most potent analog, (S)‐3‐(2,6‐dimethylphenoxy)‐1‐phenylpropan‐1‐amine (S)‐( 5 ), was six‐fold more potent than (R)‐Mex in producing a tonic block. As observed with mexiletine, the newly synthesized compounds exhibit modest enantioselective behavior, that is more evident in 3‐(2,6‐dimethylphenoxy)butan‐1‐amine ( 3 ). Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Liquid Chromatographic Resolution of Mexiletine and Its Analogs on Crown Ether‐Based Chiral Stationary Phases

Mexiletine, an effective class IB antiarrhythmic agent, and its analogs were resolved on three different crown ether‐based chiral stationary phases (CSPs), one (CSP 1 ) of which is based on (+)‐(18‐crown‐6)‐2,3,11,12‐tetracarboxylic acid and the other two (CSP 2 and CSP 3 ) are based on (3,3’‐diphenyl‐1,1’‐binaphthyl)‐20‐crown‐6. Mexiletine was resolved with a resolution (R_S) of greater than 1.00 on CSP 1 and CSP 3 containing residual silanol group‐protecting n‐octyl groups on the silica surface, but with a resolution (R_S) of less than 1.00 on CSP 2 . The chromatographic behaviors for the resolution of mexiletine analogs containing a substituted phenyl group at the chiral center on the three CSPs were quite dependent on the phenoxy group of analytes. Namely, mexiletine analogs containing 2,6‐dimethylphenoxy, 3,4‐dimethylphenoxy, 3‐methylphenoxy, 4‐methylphenoxy, and a simple phenoxy group were resolved very well on the three CSPs even though the chiral recognition efficiencies vary with the CSPs. However, mexiletine analogs containing 2‐methylphenoxy group were not resolved at all or only slightly resolved. Among the three CSPs, CSP 3 was found to show the highest chiral recognition efficiencies for the resolution of mexiletine and its analogs, especially in terms of resolution (R_S). Chirality 26:272–278, 2014. © 2014 Wiley Periodicals, Inc.     

Studies on Chrysanthemic Acid

Synthesis of (±)-trans-chrysanthemic acid from (±)-1′-hydroxydihydro-trans-chrysanthemic acid by the dehydration with p-toluene-sulfonic acid was attempted. However, the attempt was found to be unsuccessful giving a compound believed to be methyl methyl 2,6 dimethylhepta-3.6-diene-5-carboxylate upon dehydration.

A cleavage upon cyclopropane ring was confirmed by deriving the acid obtained by the hydrolysis of the above ester to already known 2,6-dimethyl-heptane-5-carboxylic acid.

Analogous mode of dehydration and cleavage upon the ester of (±)-2,2-dimethyl-3-trans-hydroxylbenzyl-cyclopropane-l-carboxylic acid was also observed to give 1-phenyl-4-methyl-penta-1,3-diene-3-carboxylic acid. On the other hand, (±)-trans-caronic acid being derived to (±)-1′-oxo-2′-hydroxy-dihydro-trans-chrysanthemic acid, the synthesis of (±)-trans-chrysanthemic acid from (±)-trans-caronic acid became possible using (±)-1′-oxo-2′-hydroxy-dihydro-trans-chrysanthemic acid as a relay substance.     

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. Chirality 26:670‐674, 2014. © 2014 Wiley Periodicals, Inc.     

Reduction of 2-Substituted Cyclohexanones by Saccharomyces Cerevisiae

An enzymatic reduction of 2-substituted cyclohexanones mediated by Saccharomyces cerevisiae was studied with respect to the stereochemical course and optical purity of the products. Reduction of ketones 1b-1f resulted in separable diastereoisomeric mixtures of cis- and trans-stereoisomers of 2-substituted cyclohexanols (2b-2f and 3b-3f) having the (S) absolute configuration at the chiral center bearing the hydroxyl functionality with high enantiomeric purity. Reduction of ketone 1a yielded mixture of cis-(1S, 2R)- and trans-(1R, 2R)-stereoisomers (2a and 3a) with lower enantiomeric purity. Changes in the nature of the C(2)-substituent affect the stereochemical course of the biotransformation. However, they significantly influenced the enantiomeric purity of the products. The diastereoselectivity of the process was studied as well; high diastereoselectivity was observed with the substrates 1a, 1e and 1f.     

Preparation and Studies of Chiral Stationary Phases Containing Enantiopure Acridino‐18‐Crown‐6 Ether Selectors

The enantiomeric separation ability of the newly prepared chiral stationary phases containing acridino‐18‐crown‐6 ether selectors was studied by high‐performance liquid chromatography (HPLC). The chiral stationary phases separated the enantiomers of selected protonated primary aralkylamines efficiently. The best results were found for the separation of the mixtures of enantiomers of NO₂‐PEA. Chirality 26:651–654, 2014. © 2014 Wiley Periodicals, Inc.     

The stereodynamics of 1,2‐dipropyldiaziridines

N‐alkylated trans‐diaziridines are an intriguing class of compounds with two stereogenic nitrogen atoms which easily interconvert. In the course of our investigations of the nature of the interconversion process via nitrogen inversion or electrocyclic ring opening ring closure, we synthesized and characterized the three constitutionally isomeric diaziridines 1,2‐di‐n‐propyldiaziridine 1 , 1‐isopropyl‐2‐n‐propyldiaziridine 2 , and 1,2‐diisopropyldiaziridine 3 to study the influence of the substituents on the interconversion barriers. Enantiomer separation was achieved by enantioselective gas chromatography on the chiral stationary phase Chirasil‐β‐Dex with high separation factors α (1‐isopropyl‐2‐n‐propyldiaziridine: 1.18; 1, 2‐diisopropyldiaziridine: 1.24; 100°C 50 kPa He) for the isopropyl substituted diaziridines. These compounds showed pronounced plateau formation between 100 and 150°C, and peak coalescence at elevated temperatures. The enantiomerization barriers ΔG? and activation parameters ΔH? and ΔS? were determined by enantioselective dynamic gas chromatography (DGC) and direct evaluation of the elution profiles using the unified equation implemented in the software DCXplorer. Interestingly, 1‐isopropyl‐2‐n‐propyldiaziridine and 1,2‐diisopropyldiaziridine exhibit similar high interconversion barriers ΔG? (100°C) of 128.3 ± 0.4 kJ mol^?1 and 129.8 ± 0.4 kJ mol^?1, respectively, which indicates that two sterically demanding substituents do not substantially increase the barrier as expected for a distinct nitrogen inversion process. Chirality, 2010. © 2009 Wiley‐Liss, Inc.     

Chiral 1,2‐Dialkenyl Diaziridines: Synthesis,Enantioselective Separation,and Nitrogen Inversion Barriers

trans‐1,2‐Disubstituted diaziridines form stable enantiomers at ambient conditions because of the two stereogenic pyramidal nitrogen atoms. Functionalized trans‐1,2‐disubstituted diaziridines can be utilized as a chiral switching moiety between two enantiomeric states in more complex molecular structures. However, the synthesis of functionalized diaziridines is quite challenging, because of the limited tolerance of reaction conditions that can be applied. Here we present a strategy to make trans‐1,2‐disubstituted diaziridines accessible as versatile building blocks in C‐C‐bond formations, i.e., the Heck reaction, and therefore introducing aryl substituents. The synthesis of trans‐1,2‐dialkenyl diaziridines with terminal alkenyl substituents and their stereodynamic properties are described. Chirality 27:156–162, 2015. © 2014 Wiley Periodicals, Inc.     

Efficient access to all four stereoisomers of phenylalanine cyclopropane analogues by chiral HPLC

Bonded polysaccharide‐derived chiral stationary phases were found to be useful for the preparation of the four stereoisomers of the cyclopropane analogue of phenylalanine (c₃Phe) as well as for the direct determination of the enantiomeric purity of c₃Phe derivatives by HPLC. Three chiral stationary phases, consisting of cellulose and amylose derivatives chemically bonded on allylsilica gel, were tested. The mixed 10‐undecenoate/3,5‐dimethylphenylcarbamate of cellulose, 10‐undecenoate/3,5‐dimethylphenylcarbamate of amylose and 10‐undecenoate/p‐methylbenzoate of cellulose were the starting polysaccharide derivatives for CSP‐1, CSP‐2, and CSP‐3, respectively. Using mixtures of n‐hexane/chloroform/2‐propanol as mobile phase on a semi‐preparative column (150 mm × 20 mm ID) containing CSP‐2, we separated about 1.7 g of racemic cis‐methyl 1‐tert‐butoxycarbonylamino‐2‐phenylcyclopropanecarboxylate (cis‐ 6 ) and 1.2 g of racemic trans‐methyl‐1‐tert‐butoxycarbonylamino‐2‐phenylcycloprop‐anecarboxylate (trans‐ 6 ) by successive injections. Chirality 11:583–590, 1999. © 1999 Wiley‐Liss, Inc.     

Schistosomicidal Activity of Dihydrobenzofuran Neolignans

We have evaluated the antischistosomal activity of synthetic dihydrobenzofuran neolignans (DBNs) derived from (±)‐trans‐dehydrodicoumaric acid dimethyl ester ( 1 ) and (±)‐trans‐dehydrodiferulic acid dimethyl ester ( 2 ) against adult Schistosoma mansoni worms in vitro. Compound 4 ((±)‐trans‐4‐O‐acetyldehydrodiferulic acid dimethyl ester) displayed the most promising activity; at 200 μm , it kills 100 ± 0% of worms after 24 h, which resembles the result achieved with praziquantel (positive control) at 1.56 μm . The hydrogenation of the double bond between C7′ and C8′, the introduction of an additional methyl group at C3′, and a double bond between C7 and C8 decreased the schistosomicidal activity of DBNs. On the other hand, the presence of the acetoxy group at C4 played an interesting role in this activity. These results demonstrated the interesting schistosomicidal potential of DBNs, which could be further exploited.     

Synthesis of ( ± )-Methyl Epijasmonate and ( ± )-Methyl Cucurbate

A novel synthesis of ( ± )-methyl epijasomonate (2) and the first synthesis of ( ± )-methyl cucurbate (4) were achieved starting from 2-allylcyclohexane-1,3-dione (8). The synthetic epimer 2 had a stronger jasmin flavor than the trans-isomer 1 with 95% purity.     

Constituents of the Argentine Liverwort Plagiochila diversifolia and Their Insecticidal Activities

Three new compounds, a bicyclogermacrene ( 1 ) and two 2,3‐secoaromadendrane esters ( 2 and 3 ), together with (13S)‐13‐hydroxylabda‐8,14‐diene ( 4 ), fusicogigantone B ( 5 ), 3α,14‐diacetoxy‐2‐hydoxybicyclogermacrene ( 6 ), fusicogigantone A ( 7 ), neofuranoplagiochilal ( 8 ), plagiochiline B ( 9 ), furanoplagiochilal ( 10 ), trans‐nerolidol, spathulenol, α‐tocopherol, and (+)‐globulol were isolated from an Argentine collection of Plagiochila diversifolia. Their structures were elucidated by extensive mono and bidimensional NMR studies. Compounds 4 , 5 , and 6 , incorporated to the larval diet at 100 μg per g of diet, reduced the larval growth of Spodoptera frugiperda (Lepidoptera: Noctuidae) by 70 ± 25, 57 ± 23, and 33 ± 16%, respectively. Compounds 4 and 5 produced 70% and 60% larval mortality at early instars. The latter also showed antifeedant properties in the Choice Test, with a feeding ratio of 0.54 ± 0.16.     

Resolution of Enantiomers of Novel C2‐Symmetric Aminobisphosphinic Acids via Diastereomeric Salt Formation With Quinine

C₂‐symmetric N,N‐bis(phosphinomethyl)amines were prepared by the thermal reaction of aromatic aldehydes with ammonia and hypophosphorus acid as previously described. Both enantiomers of C₂‐symmetric N,N‐bis(phosphinomethyl)amine were obtained in a high enantiomeric purity through the diastereomeric salt formation with (–)‐quinine, and subsequent fractional crystallization. X‐ray crystallographic analysis of one of the diastereomeric salts clearly revealed that (–)‐quinine could be an efficient resolving agent for obtaining the single enantiomer (R,R)‐N,N‐bis(phosphinomethyl)amine. Chirality 27:71–74, 2015. © 2014 Wiley Periodicals, Inc.     

Secolignans with antiangiogenic activities from Peperomia dindygulensis

Two new secolignans, peperomins G and H ( 1 and 2 , resp.), were isolated from the whole plant of Peperomia dindygulensis, together with five known secolignans, peperomin A ( 3 ), peperomin E ( 4 ), peperomin B ( 5 ), 2,3‐trans‐2‐methyl‐3‐{(3‐hydroxy‐4,5‐dimethoxyphenyl)[5‐methoxy‐3,4‐(methylenedioxy)phenyl]methyl}butyrolactone ( 6 ), 2,3‐cis‐2‐(hydroxymethyl)‐3‐{bis[5‐methoxy‐3,4‐(methylenedioxy)phenyl]methyl}butyrolactone ( 7 ). Their structures and configurations were elucidated by spectroscopic methods including 2D‐NMR techniques. Antiangiogenic effects of all compounds were evaluated using human umbilical vein endothelial cells (HUVEC) proliferation and tube‐formation tests, with compounds 4 and 5 being active in the bioassay. Compounds 4 and 5 induced obvious cell toxicity to HUVEC with IC₅₀ values of 1.64±0.19 and 8.44±0.4 μM , respectively. Compounds 4 and 5 also exhibited significant HUVEC tube formation‐inhibiting activity with IC₅₀ values of 3.13±0.09 and 6.24±0.12 μM , respectively.     

Bioactive Neolignans and Other Compounds from Magnolia grandiflora L.: Isolation and Antiplasmodial Activity

Bioassay‐guided fractionation of a methanol extract of Magnolia grandiflora against Plasmodium falciparum yielded two new ( 1 and 2 ) and six known ( 3 – 8 ) bioactive compounds. The structures of the new compounds were assigned by mass spectrometric and 1D‐ and 2D‐NMR data. Known compounds were identified by comparison of ¹H‐NMR and MS data with literature data. The two known neolignans 3 and 4 showed moderate antiplasmodial activity with the IC₅₀ values of 2.8 ± 0.1 and 3.4 ± 0.1 μm , respectively. Weak antiplasmodial activity was recorded for compounds 1 , 2 , 5 , 6 , 7 , and 8 , with the IC₅₀ values of 38 ± 2, 23 ± 2, 16.5 ± 0.2, 86 ± 1, 44 ± 4, and 114 ± 9 μm , respectively.     

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.     

High‐performance liquid chromatography separation of enantiomers of mandelic acid and its analogs on a chiral stationary phase

The enantiomers of mandelic acid and its analogs have been chromatographically separated on a chiral stationary phase (CSP) derived from 4‐(3,5‐dinitrobenzamido) tetrahydrophenanthrene. The rationale of separations of these compounds is discussed with respect to the method development for determining enantiomeric purity and possibility of obtaining enantiomerically pure materials by high‐pressure liquid chromatography. The relationship of analyte structure to the extent of enantiomeric separation has been examined and separation factors (α) are presented for various groups of structurally related compounds. Chiral recognition models have been suggested to account for the observed separations. These models provide mechanistic insights into the chiral recognition process. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Microbial Allyl Rearrangement and Resolution of Acetates of Unsaturated Cyclic Terpene Alchols by Pseudomonas sp. NOF-5 Strain

Microbial hydrolysis of the acetates of unsaturated cyclic terpene alcohols by Pseudomonas sp. NOF-5 isolated from soil was investigated. (±)-trans-Carveyl acetate ((±)-trans-3) was enantio-selectively hydrolyzed with NOF-5 strain to give ( – )-trans-carveol (( – )-trans-2 of 86.6% optical purity). However, the hydrolysis of (±)-cis-3 was less enantioselective, while (±)-piperitylacetate ((±)-6, a cis and trans mixture) was hydrolyzed to give the ( – )-trans- and ( – )-cis-piperitols (( – )- trans-5 and ( – )-cis-5) in a poor optical yield. In this case, other tert-alcohols, ( + )-trans- and ( – )- ds-2-p-menthen-1-ols ((±)-trans-7 and ( – )-cis-7), were also produced. Furthermore, microbial and enzymic allyl rearrangements of ( + )-trans-6 and ( – )-trans-verbenylacetate (( – )-trans-11) were studied. Biological treatment of (+)-trans-6 and ( – )-trans-11 with NOF-5 or its esterase gave (+)-trans- and (-)-cis-1 and ( + )-cis-3-pinen-2-ol (( + )-cis-12), respectively.     

Inhibitory Effects of Constituents of an Endophytic Fungus Hypoxylon investiens on Nitric Oxide and Interleukin‐6 Production in RAW264.7 Macrophages

Three new compounds, hypoxyloamide ( 1 ), 8‐methoxynaphthalene‐1,7‐diol ( 2 ), and hypoxylonol ( 3 ), together with seven compounds isolated from nature for the first time, investiamide ( 4 ), hypoxypropanamide ( 5 ), hypoxylonol A ( 6 ), investienol ( 7 ), 2‐heptylfuran ( 8 ), (3S)‐5‐methyl‐8‐O‐methylmellein ( 9 ), (4R)‐O‐methylsclerone ( 10 ), along with 19 known compounds, 11 – 29 , were isolated from the culture broth of Hypoxylon investiens BCRC 10F0115, a fungal endophyte residing in the stems of an endemic Formosan plant Litsea akoensis var. chitouchiaoensis. The structures of the new compounds were established by spectroscopic methods, including UV, IR, HR‐ESI‐MS, and extensive 1D‐ and 2D‐NMR techniques. Of these isolates, 2 , 8‐methoxynaphthalen‐1‐ol ( 15 ), and 1,8‐dimethoxynaphthalene ( 16 ) showed nitric oxide (NO) inhibitory activity with IC₅₀ values of 11.8±0.9, 17.8±1.1, and 13.3±0.5 μM , respectively, stronger than the positive control quercetin (IC₅₀ 36.8±1.3 μM ). Compounds 2, 15 , and 16 also showed interleukin‐6 (IL‐6) inhibitory activity with IC₅₀ values of 9.2±1.7, 18.0±0.6, and 2.0±0.1 μM , stronger than the positive control quercetin (IC₅₀ 31.3±1.6 μM ). To the best of our knowledge, this is the first report on guaiane sesquiterpene metabolites, 3, 6 , and 7 , from the genus Hypoxylon.     

Molecular tweezers for enantiodiscrimination in NMR: Di‐(R,R)‐1‐[10‐(1‐hydroxy‐2,2,2‐trifluoroethyl)‐9‐anthryl]‐2,2,2‐trifluoroethyl benzenedicarboxylates

A series of new chiral molecular tweezers, di‐(R,R)‐1‐[10‐(1‐hydroxy‐2,2,2‐trifluoroethyl)‐9‐anthryl]‐2,2,2‐trifluoroethyl phthalate (2), isophthalate (3) and terephthalate (4), were synthesized and their structure studied by NMR and molecular mechanics. Their effectiveness as chiral solvating agents for the determination of the enantiomeric purity of chiral compounds using NMR was demonstrated. Chirality 2010. © 2009 Wiley‐Liss, Inc.