Racemic Derivatives Research Articles

Development of a Radioimmunoassay for the Quantitative Determination of 8-Prenylnaringenin in Biological Matrices

Seven carboxylic acid haptens of 8-prenylnaringenin (8-PN) were synthesized, coupled to cationized bovine serum albumin, and employed to raise specific antisera in rabbits. Two linkers of different lengths (C3H6COOH and C6H12COOH) were coupled to the C7-OH group and separated into their respective enantiomers yielding the first four haptens. Racemic derivatives with C4'-OH coupled linkers C5H10COOH and C9H18COOH were synthesized carrying a methylated C7-OH. Another racemic C4'-OH hapten (CH2COOH) was prepared starting from naringenin. The haptens elicited variable antibody titers dependent on linker lengths, with short linkers giving the best results. Three antisera were characterized in detail: anti-C7-carboxy-propyloxy-2S-(-)-8-PN (anti-H-11), anti-C7-carboxy-propyloxy-2R-(+)-8-PN (anti-H-10), and anti-C4'-carboxy-methoxy-rac-8-PN (anti-H-25). anti-H-10 and anti-H-11 showed about 9% enantiomeric cross-reactivity, and anti-H-11 did not discriminate between isoxanthohumol (IX) and 8-PN (84% cross-reactivity). For anti-H-10, cross-reactivities in the range of 2-5% were found for xanthohumol, IX, and 6-prenylnaringenin. Respective numbers for anti-H-25 were 0.02, 0.1, and 0.2%. Tritiated 8-PN was synthesized yielding a 3H-tracer of high specific radioactivity (2.22 GBq/mg). A radioimmunoassay using anti-H-25 and 3H-8-PN was established and used for the quantitative determination of 8-PN in various beer brands and in the urine of six men after the consumption of three different brands of beer. Furthermore, the dose-dependent excretion of 8-PN was tested after the consumption of a higher volume of a single beer brand with and without spiking with 8-PN and a small oral dose of authentic 8-PN, respectively. Conflicting results led to a pilot test on the in vivo conversion (demethylation) of IX into 8-PN in two men. Conversion rates of 1.9 and 4.4% were estimated. Thus, the total 8-PN dose in beer brands spiced with natural hop or hop products seems to be the sum of the 8-PN amount in a consumed volume and the amount arising from the conversion of IX.

Unsymmetrical 1,n′-disubstituted ferrocenoyl peptides: convenient one pot synthesis and solution structures by CD and NMR spectroscopy

We present a systematic study on unsymmetrical amino acid derivatives of 1,1′-ferrocene dicarboxylic acid. A convenient and general one pot synthetic procedure is presented in which the unsymmetrical amino acid derivatives are readily separated by column chromatography. The following ferrocene derivatives Fe[C5H4-CO-Aaa1-OMe][C5H4-CO-Aaa2-OMe] with different amino acids were prepared and their solution structures studied by NMR and CD spectrosocopy (Aaa1 = Aaa2 = Phe, 1; Aaa1 = Aaa2 = DPhe, 1a; Aaa1 = Aaa2 = Ala, 2; Aaa1 = Phe, Aaa2 = Ala, 3; Aaa1 = DPhe, Aaa2 = Ala, 4; Aaa1 = Aaa2 = Pro, 5; Aaa1 = Aaa2 = Gly, 6; all amino acids are pure L enantiomers except where stated otherwise). NMR spectroscopy in CDCl3 confirms intramolecular hydrogen bonds for the disubstituted derivatives 1–4 and 6. CD spectra were recorded for all derivatives in CH2Cl2. They clearly show a P helical isomer of the ferrocene moiety for the L amino acid derivatives 1–3 and M helicity for the DPhe derivative 1a. The racemic derivative 6 shows only intermolecular interactions, while the Pro derivative 5, which is devoid of amide protons, most likely exists in an “open conformation”. Most importantly, the unsymmetrical mixed D,L derivative 4 has only a weak CD signal in the ferrocene region which is interpreted as an equilibrium between the P and M helical isomers with a slight excess of the latter.

A Straightforward and Efficiently Scaleable Synthesis of Novel Racemic 4-Substituted-2,8-diazaspiro[4.5]decan-1-one Derivatives

Novel and straightforward syntheses (3-5 steps, high yields) of racemic diazaspiropiperidine derivatives based on the Michael addition of pipecolate-derived enolates to a range of nitroalkenes have been developed. The reaction has been shown to have a general scope and can be conducted on a preparatively useful scale. Isolation and identification of diazaspiropiperidine enantiomers was efficiently achieved using normal phase chiral HPLC.

Optical resolution by crystallization from melt using enantiomer derivatives as resolving agents: Nonlinear behavior of resolving agent mixtures

Substituted racemic 1-phenylethylamine derivatives were reacted in molten phase with chiral N-substituted 1-phenylethylamine dicarboxylic acid derivatives (4-9), and their mixtures (e.g., 4+6, 7+8, etc.) in different ratios, and the crystalline quasi-racemic diastereomers so formed were separated. Nonlinear behavior of the mixtures of resolving agents having related structure and considerable positive and negative chiral-chiral interactions were observed.

Synthesis and transformations of a pyrazole containing alpha, beta-didehydro-alpha-amino acid derivatives.

2H-Pyran-2-ones 1 were transformed with various hydrazines into (E)- or (Z)-alpha, beta-didehydro-alpha-amino acid (DDAA) derivatives 4 (and 7) containing a highly substituted pyrazolyl moiety attached at the beta-position. With heterocyclic hydrazines, the products 4 were accompanied also by decarboxylated enamines E-6. In order to separate (E/Z)-mixtures of acids, they were transformed to the corresponding methyl esters 9 and 10 by the application of diazomethane. Catalytic hydrogenation under high pressures with Pd/C as a catalyst resulted in the formation of racemic alanine derivatives 11.

Kinetic Resolutions of Indan Derivatives Using Bacteria

Racemic indan derivatives have been resolved by the hydrolysis of amide bonds using Corynebacterium ammoniagenes IFO12612 to produce (S)-amine and (R)-amides. In the kinetic resolution of 1 (N-12-(6-methoxy-indan-1-yl)ethyl]acetamide), it was possible to run the reaction to 44% conversion on a 10-g scale, obtaining (S)-amine 4 ((S)-2-(6-methoxy-indan-1-yl)ethylamine) at >99% enantiomeric excess (ee) and (R)-1 at 98% ee.

NEW ROUTES TO α-AMINO ACID β,γ-THIOENOL ETHER DERIVATIVES

ABSTRACT Racemic derivatives of α-amino acid β,γ-thioenol ethers have been synthesized from homoserine through a γ-elimination on a sulfoxide derived from aspartaldehyde. Optically active derivatives were efficiently prepared from L-methionine by a Pummerer like reaction.

Functionalised organosulfur donor molecules: synthesis of racemic hydroxymethyl-, alkoxymethyl- and dialkoxymethyl-bis(ethylenedithio)tetrathiafulvalenes

Abstract Short synthetic routes to racemic derivatives of bis(ethylenedithio)tetrathiafulvalene carrying one hydroxymethyl (HMET), alkoxymethyl or dialkoxymethyl side chain are reported along with cyclic voltammetry measurements and conversion of HMET to (2:1) radical cation salts.

Normal-Phase TLC Separation of Enantiomers of 1.4-Dihydropyridine Derivatives

A new TLC-based method was proposed for the separation of enantiomers and mixtures of racemic DHP derivatives differing in the kind of substituent in the phenyl ring. The conditions for the effective determination of the substances involved and the mechanism of their sorption were also studied. For the separation of felodipine, nilvadipine, and isradipine enantiomers, thin-layer chromatography was used, with a chiral stationary phase of the ligand exchange type, and developing phases of a different concentration of methanol (Φ) as an organic modifier. The retention coefficient values k′ were used to make the plots log k′ = f (log Φ) and log k′ = f (Φ). The processes taking place in the chromatographic systems were shown to be described by the Snyder–Soczewiński equation.

Xanthen-9-ylidene protecting groups in glycerol chemistry

The preparation of racemic, (S)- and (R)-1,2-O-(xanthen-9-ylidene)glycerol 17a, 20a and 23a and racemic, (S)- and (R)-1,2-O-(2,7-dimethylxanthen-9-ylidene)glycerol 17b, 20b and 23b is reported. The racemic derivatives 17a and 17b are converted into their stearate esters, which are then treated with dichloroacetic acid and pyrrole under mild conditions to give racemic 1-O-stearoylglycerol 25 in good yield. The xanthen-9-ylidene and 2,7-dimethylxanthen-9-ylidene residues are incorporated into 9,9-di(pyrrol-2-yl)xanthene 36 and 2,7-dimethyl-9,9-di(pyrrol-2-yl)xanthene 37. These by-products are easily removed by treatment with iron(III) chloride in diethyl ether solution. What are believed to be enantiomerically pure (R)- and (S)-1-O-stearoylglycerol 28 and 5 are similarly prepared in good yields from (S)- and (R)-1,2-O-(xanthen-9-ylidene)glycerol 20a and 23a.

Metabolic Production of Amphetamine Following Administration of Clobenzorex

Many of the anorectic drugs that are metabolized to amphetamine and/or methamphetamine pose significant concerns in the interpretation of amphetamine-positive drug testing results. One of these drugs--clobenzorex--has been shown to produce amphetamine. Thirty milligrams of clobenzorex hydrochloride, in the form of a single Asenlix capsule (Roussel, Mexico), were administered orally to five human volunteers with no history of amphetamine, methamphetamine or clobenzorex use. Following administration, urine samples (total void volume) were collected ad lib for seven days and pH, specific gravity and creatinine values were determined. To determine the excretion profile of amphetamine and parent drug, samples were extracted, derivatized, and analyzed by gas chromatography/mass spectrometry (GC/MS) using a standard amphetamine procedure with additional monitoring of ions at m/z 91, 118, 125 and 364 for the detection of clobenzorex. Peak concentrations of amphetamine were detected at 4 to 19 h postdose and ranged from approximately 715 to 2474 ng/mL amphetamine. Amphetamine could be detected (> 5 ng/mL) in the urine in one subject for up to 116 h postdose. GC/MS was also used to determine the enantiomeric composition of the metabolite, amphetamine. This analysis revealed the metabolically derived amphetamine was only the d-enantiomer. This differs from previous literature which indicates clobenzorex is the racemic N-orthochlorobenzyl derivative of amphetamine.

Resolution of derivatives of 1,2-propanediol with lipase B from Candida antarctica: Effect of substrate structure, medium, water activity and acyl donor on enantiomeric ratio

The glycerol-related racemic derivatives 1a–15a and 1b–15b have been resolved by hydrolysis and transesterifications using lipase B from Candida antarctica. Influence of substrate structure for the enantiomeric ratio E has been explained on the basis of previous molecular modelling. E values and equilibrium constants K eq have been calculated on the basis of ee s and ee p measured throughout the reaction, and ping-pong bi-bi mechanism using the computer program E&K calculator. Medium effects have been studied for hydrolysis with organic co-solvents and transesterifications in different solvents with varying water activity, a w. For some substrates addition of 30% acetone to the hydrolysis reaction gave a large increase of E. High water activity gave for some substrates an increase of E, but was unfavourable for the reversibility. However, this did not significantly influence the ee of product fraction. The influence of the alkoxy part of various butanates as acyl donors has been studied with respect to E and K eq. It was generally found that 2-chloroethyl butanate gave higher E than vinyl butanate; however, the latter gave irreversible conditions.

A Further Synthesis of an Analogue of the Antifungal/Antiherbivore Lipid from Avocado

A further synthesis of the saturated racemic derivative (1b) of the avocado diene (1a) ((R,Z,Z)-2-hydroxy-4-oxohenicosa-12,15-dien-1-yl acetate; "persin") is described.

Synthesis, Enantioselective Separation, and Identification of Racemic Tetralin, Indan, and Benzosuberan Derivatives

Forty chiral substituted tetralins, indans, and benzosuberans were synthesized and resolved by gas chromatography using a chiral stationary phase. The substituent groups include hydroxy, keto, methyl, and methoxy moieties. These types of compounds are known to be biological markers in fossil fuels as well as important intermediates in organic synthesis. Total ion current mass spectrometry was used to detect and identify the separated analytes. Two different derivatized cyclodextrin chiral stationary phases (having somewhat different enantioselectivities) were used. The ring size of the analyte appears to affect enantioresolution. The MS relative ion abundance and/or fragmentation patterns can be used to distinguish between enantiomeric and diastereomeric analytes.

Reactions of the ketone derived from (±)-3,4,5-tri- O-benzyl-1,2- O-isopropylidene- myo-inositol: preparation of racemic derivatives of epi-inositol and of 4- C-methyl- epi- [(±)- iso-laminitol] and 4- C-methyl- myo-inositol [(±)-laminitol

Oxidation of (±)-3,4,5-tri- O-benzyl-1,2- O-isopropylidene- myo-inositol with the pyridine-SO 3 complex in methyl sulfoxide gave the ketone which was reduced with sodium borohydride to give almost exclusively the corresponding epi-inositol derivative. Reaction of the ketone with diazomethane gave an epoxide which was reduced with lithium aluminium hydride to give a 4- C-methyl- myo-inositol derivative and reaction of the ketone with methyl magnesium iodide gave the isomeric 4- C-methyl- epi-inositol derivative.

Nucleophilic substitution on α-mesyloxy-O-alkyloximes—I. Enantiospecific synthesis of 2-(imidazol-1-yl)-1,3-diphenylpropan-1-one O-alkyloximes

An enantiospecific synthesis of (S)- and (R)-(E)-5-[1,3-diphenyl-2-(imidazol-1-yl)propylidene] aminooxypentanoic acids 1 using homochiral phenylalanines as starting material is described. Chiral α-hydroxyketones 9 were obtained from α-hydroxyacids 7 by Weinreb's ketone synthesis. Imidazole introduction by nucleophilic substitution on mesylate 10 led to 2-(imidazol-1-yl)propan-1-one derivative 3, key intermediate in the synthesis of 1. However, the low configurational stability displayed by compound 3 compromised its use in an enantiospecific synthesis. Homochiral compounds 1 were then obtained by a nucleophilic substitution on α-mesyloxy-O-alkyloxymes 14 which were in turn obtained from 9. This nucleophilic substitution on α-mesyloxy-O-alkyloxymes was not previously reported either on homochiral compounds or on racemic derivatives.

Carbocyclic Phosphonate-Based Nucleotide Analogs Related to PMEA II. Racemic cis-Configured Derivatives

Racemic N-(cis-2-phosphonomethoxycycloalkyl) derivatives of heterocyclic bases, a novel type of nucleotide analogs related to 9-(2-phosphonomethoxyethyl)adenine (PMEA), are reported. The synthesis of adenine- (6a, 6b), uracil- (6c) and cytosine- (6d) containing carbocyclic phosphonates is based on the reaction of cis-2-hydroxycycloalkyl derivatives of protected nucleobases with diisopropyl tosyloxymethanephosphonate. The starting purine-containing nucleoside analogs 5a-5f were prepared by the Mitsunobu reaction of protected nucleobases with trans-2-benzyloxycycloalkanols, whereas pyrimidine-containing nucleoside analogs 5g-5k were obtained by configurational inversion at C-2' of the corresponding 1-(trans-2-hydroxycycloalkyl)pyrimidines via ring opening of their 2,2'-anhydro derivatives.

Conformational analysis of 5-lipoxygenase inhibitors: role of the substituents in chiral recognition and on the active conformations of the (methoxyalkyl)thiazole and methoxytetrahydropyran series.

The investigation of the SAR of 5-lipoxygenase (5-LO) inhibition of a series of racemic (methoxyalkyl)thiazoles, exemplified by compound 7 (ZM-211965), has led to other active, racemic derivatives in which the thiazole moiety has been replaced by an ester or an ether. Furthermore, the cyclization of the ethers has given a highly potent, but achiral series, the methoxytetrahydropyrans (methoxyTHP), exemplified by 41 (ZD-2138) presently under clinical evaluation. More recent structural investigations have led to chiral members of this series bearing a 2-methyl substituent in the tetrahydropyran ring. The potential for enantioselectivity in each of the three noncyclic, racemic series led us to synthesize the pure enantiomers ((R)-13c, (S)-13c, (R)-13d, (S)-13d, (R)-15c, (S)-15c, (R)-16b, (S)-16b, and (R)-16c, (S)-16c) and to determine their absolute configuration. The biological activity of each enantiomer was evaluated in intact mouse macrophages and in human whole blood and showed that, of these three series, only the thiazole is enantioselective and that the active configuration is (S) (being between 2 and 3 orders of magnitude more potent than the (R) isomer in mouse macrophages). Conformational analysis using systematic conformational searching, molecular mechanics, and semiempirical methods has been performed on the chiral compounds, and the results have helped to explain the enantioselectivity in the thiazole series and to define the role of the substituents around the quaternary carbon. Simultaneously in the achiral tetrahydropyran (THP) series, the critical role of the methoxy substituent has been examined through the synthesis of the ethyl (24b), ester (22b), methoxymethyl ether (26), hydroxymethyl (25b), aldehyde (27b), ketone (29b), hydroxy (31b), and methyl (23b) analogues and by analysis of their biological and conformational properties. This approach, complemented by the results of a similar study carried out on the Z and E isomers of the chiral ethyl-2-methylTHP derivative (39b and 40b), has also led to the characterization of the active conformation in this series. The whole study has identified new elements to clarify the 3D structural requirements of the 5-LO active site.

Stereoselective synthesis of 7-substituted jasmonic acid derivatives and investigation of their biological activity

Racemic 7-substituted derivatives of methyl jasmonate have been synthesized. Methyl 7-epi-methyljasmonate 3 was also synthesized in enantiomerically pure form in 7 steps from the Hajos–Wichert ketone 8. In addition the biological activity of the prepared compounds has been investigated for the induction of tendril coiling in Bryonia dioica and the elicitation of the phytoalexin production in Eschscholtzia californica. All the synthesized compounds showed poor activity in the bioassays. The specificity of the investigated species towards methyl 7-epi-jasmonate 1 seems to be very high.

Liquid Crystalline Behavior of Racemic Azobenzene Derivatives

Abstract This paper deals with the synthesis of two series of racemic azobenzene derivatives of general formula: Using differential scanning calorimetry, optical microscopy and x-ray diffraction, the thermotropic liquid crystalline polymorphism of several methyl and chloro derivatives is studied: nematic, smectic A and monotropic smectic C mesophases are described.