Efficient resolution of the dihydrodiol derivatives of benzo[a]pyrene by high-pressure liquid chromatography of the related (−)-dimenthoxyacetates

The diastereomeric (−)-dimenthoxyacetate derivatives of (±)-trans-7,8-dihydroxy-7,8-dihydrobenzo[a]pyrene were efficiently resolved by high-pressure liquid chromatography (HPLC) on silica gel. Treatment with methanolic ammonia under mild conditions removed the menthoxyacetate groups to furnish the optically pure (+) and (−) enantiomers of the trans-dihydrodiol. Epoxidation of each of the latter with m-chloroperbenzoic acid gave the corresponding (−) and (+) anti-diolepoxides. The speed and efficiency of resolution of these relatively sensitive compounds by HPLC demonstrates the potential utility of this technique for resolution of all types of carcinogen-derived arene dihydrodiols.     

Stereochemistry of the Reductive Amination of 4-Oxoproline Derivatives with Glycine Esters

An amination of 4-oxoproline derivatives with glycine methyl or benzyl ester and sodium cyanoborohydride led to the mixtures of corresponding diastereomeric 4-cis- and 4-trans-glycinoproline derivatives. We found that the ratio of diastereomers mainly depends on the structure of 4-oxoproline ester groups and, to a lesser extent, on the structure of N-acyl substituents. The best results were achieved with tert-butyl ester group; it ensured good yields of the amination products and the greatest prevalence of 4-cis-isomers. The structure of ester group in glycine molecule only scarcely affected the resulting ratio of N-(N-benzyloxycarbonylglycyl)-4-glycinoprolines.     

Preparation of Aroma Compounds by Microbial Transformation of Isophorone with Aspergillus niger

( ± )-cis-γ-Irone (1a), ( ± )-cis-dihydro-γ-irone (2a) and their trans- isomers (1b, 2b) were synthesized via 3,3-(Claisen) or 2,3-sigmatropic rearrangement of 1-hydroxymethyl-3,3,4- trimethyl-1-cyclo he xene (8) derivatives as each key step.     

Chiral nuclear magnetic resonance shift reagents: Lanthanide mixtures with 1-(1-naphthyl) ethylurea derivatives of amino acids

Esters of 1-(1-naphthly)ethylurea derivatives of L-valine, L-leucine, L-tert-leucine, and L-proline are examined as organic-soluble chiral nuclear magnetic resonance (NMR) resolving agents. The reagents are useful for resolving the spectra of chiral sulfoxides, amines, alcohols, and carboxylic acids. Enantiomeric resolution is caused by a combination of diastereomeric effects and the different association constants of the substrates with the resolving agents. Organic-soluble lanthanide species are added to resolving agent-substrate mixtures and often enhance the enantiomeric resolution. The enhancement occurs because the substrate that exhibits weaker binding with the resolving agent is more available to bond to the lanthanide. Broadening in the spectra with lanthanides is reduced at 50°C. Enantiomeric resolution is still observed at elevated temperatures. Chirality 9:1–9, 1997. © 1997 Wiley-Liss, Inc.     

Synthesis of stereoisomers of antithrombotic nipecotamides

The stereoisomers of α,α′-bis[3-(N,N-diethylcarbamoyl)-piperidino]-p-xylene ( 1 ) were synthesized. Rac ethyl nipecotate was resolved by diastereomeric (-)-D - and (+)-L-tartrate salt formation. The enantiomeric esters were hydrolyzed to the corresponding nipecotic acids, which were then converted into t-BOC derivatives. Treatment of the latter with diethylamine/isobutyl chloroformate and removal of the t-BOC protecting group afforded (R)- and (S)-N,N-diethylnipecotamides. Condensation of the latter with α,α′-dibromo-p-xylene gave (R,R)- and (S,S)- 1 . The meso-diastereomer was obtained by stereospecific synthesis in addition to our earlier procedure involving fractional crystallization of the diastereomeric mixture obtained by synthesis. The latter was resolved earlier into 1A , 1B , and 1C using chiral high-performance liquid chromatography (HPLC). Based on the stereospecific synthesis now achieved, 1A and 1B are assigned the configurations, (R,R) and (S,S) respectively, and 1C is assigned the meso configuration. The (R,S) structure of the latter is also confirmed by X-ray crystallography. © 1995 Wiley-Liss, Inc.     

Application of (S)-N-(4-Nitrophenoxycarbonyl) phenylalanine methoxyethyl ester as a chiral derivatizing reagent for reversed-phase high-performance liquid chromatographic separation of diastereomers of amino alcohols, non-protein amino acids, and PenA

Indirect enantioresolution of 15 primary and secondary amino group containing compounds (amino alcohols, non-protein amino acids, PenA) was done using the reagent (S)-N-(4-Nitrophenoxycarbonyl) phenylalanine methoxyethyl ester [(S)-NIFE] by reversed-phase high-performance liquid chromatography. The diastereomeric derivatives were analyzed under reversed-phase conditions using linear gradient. The detection was at 205 nm and sharp peaks were obtained. The reagent used is comparatively economic than the other derivatizing reagents. Method validation was also done.     

Enzymic Resolution of (± )-Unsaturated Cyclic Terpene Alcohols via Asymmetric Hydrolysis of Corresponding Acetates by Microorganisms

Asymmetric hydrolysis of the acetates of (±)-cis and trans-carveols by microorganisms or their esterase produced chiral cis and trans-carveols and the acetates of their enantiomers. The enantioselectivity of the microbial hydrolysis and the optical purities of the products varied with the species of microorganisms. This method was also applied in separation of diastereomeric mixtures of (?)-carveols and (?)-7-epi-α-cyperols.     

Stereoselective determination of fenfluramine enantiomers in rat liver microsomal incubates

An enantioselective assay for l- and d-fenfluramine in rat liver microsomal incubates was developed. The method involves extraction of fenfluramine from the microsomal incubates, and formation of fenfluramine diastereomeric derivatives with the chiral reagent S-(−)-N-trifluoroacetyl prolyl chloride. Separation and quantitation of the diastereomeric fenfluramine derivatives are carried out by a capillary gas chromatographic system with flame ionization detection. The assay is linear from 1 to 50 μg/ml for each enantiomer. The analytical method affords average recoveries of 92.28 and 96.44% for l- and d-fenfluramine, respectively. The limits of detection and quantitation for the method are 0.1 and 1.0 μg/ml for the l- and d-fenfluramine isomers, respectively. The reproducibility of the assay was <10% (RSD). The method allowed study of the depletion of l- and d-fenfluramine in rat liver microsomal incubates. The stereoselectivity of fenfluramine phase I metabolism was observed.     

Chemical synthesis of the 17-propanamide derivatives of stereoisomeric Δ14-17α- and 17β-estradiols: potential 17β-hydroxysteroid dehydrogenase inhibitors

The 17-propanamide derivatives of diastereomeric Δ¹⁴-17α- and 17β-estradiols, the potential candidates of a 17β-hydroxysteroid dehydrogenase (17β-HSD) inhibitor, were synthesized in 11 steps from estrone. The principal reactions employed involved in (1) conversion of estrone to the corresponding Δ¹⁴-estrone, (2) Grignard reaction of Δ¹⁴-estrone with allylmagnesium bromide followed by regioselective hydroboration of the resulting stereoisomeric 17ξ-allyl-Δ¹⁴-17ξ-ols with 9-borabicyclo[3.3.1]nonane (9-BBN), and (3) direct amidation of the 17ξ-O-/17ξ-C-spiro-γ-lactones with NH₃ under positive pressure of H₂.     

Improved synthesis and the crystal structure of methyl 4,6-dideoxy-4-(3-deoxy- -glycero-tetronamido)-α- -mannopyranoside, the methyl α-glycoside of the intracatenary repeating unit of the O-polysaccharide of Vibrio cholerae O:1

The crude product of deamination of the commercially available -homoserine was acetylated and the 2-O-acetyl-3-deoxy- -glycero-tetronolactone (18) formed was used to N-acylate methyl perosaminide (methyl 4-amino-4,6-dideoxy-α- -mannopyranoside, 12) and its 2,3-O-isopropylidene derivative. The major product isolated from the reaction was the crystalline methyl 4-(4-O-acetyl-3-deoxy- -glycero-tetronamido)-4,6-dideoxy-α- -mannopyranoside (1, 70–75%) resulting from acetyl group migration in the initially formed 2'-O-acetyl derivative. O-Deacetylation of 1 gave the title amide 2. Compound 2, obtained crystalline for the first time, was fully characterized, and its crystal structure was determined. Deoxytetronamido derivatives diastereomeric with 1 and 2, respectively, were obtained by the acylation of 12 with 2-O-acetyl-3-deoxy- -glycero-tetronolactone (prepared from -homoserine), and subsequent deacetylation. Structures of several byproducts of the reaction of 12 with 18 have been deduced from their spectral characteristics. Since these byproducts were various O-acetyl derivatives of 2, the title compound could be obtained in ≈ 90% yield by deacetylating (Zemplén) the crude mixture of N-acylation products, followed by chromatography.     

Arbutin derivatives from the buds of Vaccinium dunalianum and their MS/MS spectrometric fragmentations

Four arbutin derivatives were isolated from the buds of Vaccinium dunalianum in which 4-hydroxyphenyl-6′-(3''-O-β-D-glucopyranosyl-4''-hydroxycinnamoyl)-O-β-D-glucopyranoside (1) was a new compound. The structure of the new compound was determined on the basis of NMR and HR-ESI-MS data. All the arbutin derivatives were subjected to the MS/MS analyses from which the MS/MS spectrometric fragmentations were summarized.     

Enantiopure O‐Ethyl Phenylphosphonothioic Acid: A Solvating Agent for the Determination of Enantiomeric Excesses

An improved method, which is highly reproducible, was developed for the enantioseparation of racemic O‐ethyl phenylphosphonothioic acid ( 1a ) with brucine by introducing seeding to a supersaturated solution of the diastereomeric salt mixture. The present method gave both diastereomeric salts in high yields with a diastereomeric ratio of >99.5:0.5 upon choosing the crystallization solvent (MeOH for the ( (R)-1a salt and MeOH/H₂O for the ( (S)-1a salt). The enantiopure acid (R)-1a , (S)-1a showed a good chirality recognition ability for not only strong bases, such as amines and amino alcohols, but also weakly basic alcohols and was applicable as a solvating agent to the ¹H NMR determination of the enantiomeric excess of chiral amines, amino alcohols, and alcohols, including aliphatic substrates. Chirality 26:614–619, 2014. © 2014 Wiley Periodicals, Inc.     

Double Stereodifferentiation in the Asymmetric Dihydroxylation of Optically Active Olefins

A study of the stereochemical control on the asymmetric dihydroxylation of the double bond of optically active vinyl epoxides and their derivatives (bromo derivatives, azido derivatives, and vinyl aziridines) was carried out and the obtained results are herein reported. The most interesting results were obtained on trans α,β‐unsaturated epoxy esters, which were successfully converted with a diastereomeric ratio >80% into the corresponding diols using either the matched or the mismatched conditions, depending on the ligand used. Unprotected bromo derivatives and unprotected aziridines did not afford significant results, while for the protected bromo derivatives, azido derivatives, and N‐Boc protected aziridines the matched conditions led to a diastereomeric ratio >95%. Chirality 28:387–393, 2016. © 2016 Wiley Periodicals, Inc.     

Synthesis of 2-Bromomethyl-3-Hydroxy-2-Hydroxymethyl-Propyl Pyrimidine and Theophylline Nucleosides Under Microwave Irradiation. Evaluation of Their Activity Against Hepatitis B Virus

Alkylation of 2-methylthiopyrimidin-4(1H)-one (1a) and its 5(6)-alkyl derivatives 1b–d as well as theophylline (7) with 2,2-bis(bromomethyl)-1,3-diacetoxypropane (2) under microwave irradia-tion gave the corresponding acyclonucleosides 1-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]-2-methyl-thio pyrmidin-4(1H)-ones 3a–d and 7-[(3-acetoxy-2-acetoxymethyl-2-bromomethyl)prop-1-yl]theophylline (8), which upon further irradiation gave the double-headed acyclonucleosides 1,1 ′-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis[(2-(methylthio)-pyrimidin-4(1H)-ones] 4a–c, and 7,7 ′-[(2,2-diacetoxymethyl)-1,3-propylidene]-bis(theophylline) (9). The deacetylated derivatives were obtained by the action of sodium methoxide. The activity of deacetylated nucleosides against Hepatitis B virus was evaluated. Compound 5b showed moderate inhibition activity against HBV with mild cytotoxicity.     

Development of Chiral Building Blocks Having a Bicyclo[3.3.0]Octane Framework Using a Diastereomeric Resolution‐Selective Deprotection

A protocol is presented for an efficient and practical approach to the synthesis of enantiomerically pure bicyclo[3.3.0]octane derivatives from achiral C_s‐symmetric bicyclo[3.3.0]octane‐2,8‐dione using a diastereomeric resolution‐selective deprotection method. This method affords chiral building blocks having bicyclo[3.3.0]octane framework with the same site of diastereotopic carbonyl functional group. Chirality 27:364–369, 2015. © 2015 Wiley Periodicals, Inc.     

Efficient resolution of venlafaxine and mechanism study via X‐ray crystallography

Numbers of resolving factors were investigated to improve resolution of venlafaxine 1 . An effective resolving agent, O,O′‐di‐p‐toluoyl‐(R, R)‐tartaric acid 2 , was screened using similar method of ‘Dutch resolution’ from tartaric acid derivatives. The resolution efficiency was up to 88.4%, when the ratio of rac‐ 1 and 2 was 1:0.8 in THF with little water (10:1 v/v). Enantiomerically pure venlafaxine was prepared with 99.1% ee in 82.2% yield. The chiral resolution mechanism was first explained through X‐ray crystallographic study. One diastereomeric salt with well solubility forms a columnar supramolecular structure as the acidic salt (R)‐ 1 · 2 , while the other diastereomeric salt with less solubility forms a multilayered sandwich supramolecular structure by enantio‐differentiation self‐assembly as the neutral salt 2(S)‐ 1 · 2 . The water molecules play a key role in the optical resolution, as indicated by the special structures of the diastereomeric salts.     

Optical Resolution and Optimization of (R,S)‐Propranolol Using Dehydroabietic Acid Via Diastereomeric Crystallization

The optical resolution of (R,S)‐propranolol by the diastereomeric crystallization method was successfully performed using dehydroabietic acid (DHAA) as the resolving agent in methanol. The three important parameters: DHAA amount, solvent (methanol) amount, and crystallization temperature of diastereomeric salts were optimized employing the response surface methodology (RSM). When maintaining a lower limit of 95% for the purity of (S)‐propranolol, the optimal resolution conditions were a DHAA/(R,S)‐propranolol molar ratio of 1.1, solvent/(R,S)‐propranolol ratio of 16.2 mL.g^‐1, and crystallization temperature of –5 °C. The desired (S)‐propranolol was prepared with 94.8% optical purity and 72.2% yield under the optimal conditions. Chirality 27:131–136, 2015. © 2014 Wiley Periodicals, Inc.     

The arbuscular mycorrhizal fungus, Glomus intraradices, induces the accumulation of cyclohexenone derivatives in tobacco roots

Tobacco (Nicotiana tabacum L.) plants were grown with and without the arbuscular mycorrhizal fungus, Glomus intraradices Schenk & Smith. High-performance liquid chromatographic analyses of methanolic extracts from mycorrhizal and non-mycorrhizal tobacco roots revealed marked fungus-induced changes in the patterns of UV-detectable products. The UV spectra of these products, obtained from an HPLC photodiode array detector, indicated the presence of several blumenol derivatives. The most predominant compound among these derivatives was spectroscopically identified as 13-hydroxyblumenol C 9-O-gentiobioside (“nicoblumin”), i.e. the 9-O-(6′-O-β-glucopyranosyl)-β-glucopyranoside of 13-hydroxy-6-(3-hydroxybutyl)-1,1,5-trimethyl-4-cyclohexen-3-one, a new natural product. This is the first report on the identification of blumenol derivatives in mycorrhizal roots of a non-gramineous plant. Received: 28 August 1998 / Accepted: 26 October 1998     

Relationship between Stereoisomerism and Biological Activity of Pyrethroids

(+)-trans-Homochrysanthemic acid, when boiled in dilute sulfuric acid, gives (+)-trans-ε-hydroxy-dihydrohomochrysanthemic acid, m.p. 176–7°, together with (+)-δ, δ-dimethyl-γ-isobutenyl-δ-valerolactone. The formation of optically active lactone from (+)-trans-homochrysanthemic acid provides another cogent evidence for the structure of the lactone previously deduced on the racemic compound.

The Arndt-Eistert reaction of the homo-acids give further higher homologues such as (±)-,(+)-trans-β-(3-isobutenyl-2, 2-dimethylcyclopropane-1)-propionic acids and (±)-cis-3-isobutenyl-2, 2 dimethylcyclobutane-1-acetic acid. Both trans-acids, in boiling dilute sulfuric acid, give the same (±)-γ-(1′, 1′, 4′-trimethyl-pent-2′-enyl)-butyrolactone together with the corresponding hydroxy-acids, optically inactive and active, respectively.

Complete resolution of (±)-trans-homochrysanthemic acid and (±)-trans-β-(3-isobutenyl-2, 2-dimethycyclopropane-1)-propionic acid was achieved by means of optically active α-phenylethylamine.     

Optical Rotatory Dispersion of Rotundifolone

Microbial (enzymatic) hydrolysis of (±)-O-acetyl allethrolone gave (?)-(R)-allethrolone with (+)-(S)-O-acetyl allethrolone. And microbial hydrolysis of (±)-cis and trans-2-allylcyclopentyl acetates gave the low optically active cis and trans-2-allylcyclopentanols with the acetates of their antipodes. Also, the acetates of (±)-primary alcohols with cyclopropane and cyclohexene rings: (±)-chrysanthemyl alcohol, α-cyclogeraniol, were hydrolyzed by microorganisms to give the optically active alcohols in low optical purities Further, synthesis and microbial resolution of racemic hydroxy-trimethylcyclohexanones, useful intermediate for synthesis of compounds related to carotenoids, were tried.