Bromolactamization: Key Step in the Stereoselective Synthesis of Enantiomerically Pure,cis‐Configured Perhydropyrroloquinoxalines

Compounds based on the pyrroloquinoxaline system can interact with serotonin 5‐HT₃, cannabinoid CB₁, and μ‐opioid receptors. Herein, a chiral pool synthesis of diastereomerically and enantiomerically pure bromolactam (S,R,R,R)‐ 14A is presented. Introduction of the cyclohexenyl ring at the N‐atom of (S)‐proline derivatives 8 or methyl (S)‐pyroglutamate ( 12 ) led to the N‐cyclohexenyl substituted pyrrolidine derivatives 4 and 13 , respectively. All attempts to cyclize the (S)‐proline derivatives 4 with a basic pyrrolidine N‐atom via [3 + 2] cycloaddition, aziridination, or bromolactamization failed. Fast aromatization occurred during treatment of cyclohexenamines under halolactamization conditions. In contrast, reaction of a 1:1 mixture of diastereomeric pyroglutamates (S,R)‐ 13bA and (S,S)‐ 13bB with LiO^tBu and NBS provided the tricyclic bromolactam (S,R,R,R)‐ 14A with high diastereoselectivity from (S,R)‐ 13bA , but did not transform the diastereomer (S,S)‐ 13bB . The different behavior of the diastereomeric pyroglutamates (S,R)‐ 13bA and (S,S)‐ 13bB is explained by different energetically favored conformations. Chirality 26:793–800, 2014. © 2014 Wiley Periodicals, Inc.     

A practical and efficient method for the resolution of 3‐phospholene 1‐oxides via coordination complex formation1

A simple, efficient, and economical method based on the combination of the exceptional behavior of o,o′‐dibenzoyl‐ or o,o′‐di‐p‐toluyl‐(2R,3R)‐tartaric acid in chiral recognition processes, and the coordination ability of calcium or magnesium ion was developed for the resolution of phospholene oxides 1 . The calcium or magnesium salt of (?)‐o,o′‐dibenzoyl‐(2R,3R)‐tartaric acid 2 , 4 ‐ 6 or calcium hydrogen (?)‐o,o′‐di‐p‐toluyl‐(2R,3R)‐tartrate 3 may form crystalline diastereomeric coordination complexes with the appropriate antipode of substituted 3‐phospholene oxides 1 that makes possible efficient resolutions. Optically active phospholene oxides 1 were prepared directly by simply crystallization and digestion of the corresponding diastereomeric complexes so formed. Thermal behavior of the crystalline diastereomeric complexes was studied by simultaneous TG/DTA. The novel method may be of more general value in respect of the resolution of tertiary phosphine oxides. Chirality, 2010. © 2010 Wiley‐Liss, Inc.     

Synthesis and nootropic activity of some 2,3-dihydro-1H-isoindol-1-one derivatives structurally related with piracetam

Three 2,3‐dihydro‐1H‐isoindol‐1‐ones structurally related with piracetam (=2‐oxopyrrolidine‐1‐acetamide) have been synthesized and tested for their nootropic effects in the passive avoidance test in mice. Compounds (RS)‐ 2 , (R,R)‐ 3 , and (R,S)‐ 3 were obtained in good yields in only two steps starting from methyl dl ‐phthaloylalanine. Compound (RS)‐ 2 exhibited nootropic activity at lower doses than piracetam, used as reference drug, but it showed lower efficacy. Whereas diastereoisomers (R,R)‐ 3 and (R,S)‐ 3 were as potent as piracetam to revert amnesia induced by scopolamine, (R,S)‐ 3 showed lower efficacy than (R,R)‐ 3 . Only (R,R)‐ 3 showed myorelaxant effect at doses of 10 and 30 mg/kg; other compounds did not exhibit any anticonvulsant, sedative, myorelaxant, or impaired motor‐coordination effect in mice. These synthesized 2,3‐dihydro‐1H‐isoindol‐1‐one derivatives constitute a new kind of nootropic compounds.     

Synthesis of enantiopure planar chiral bis‐(para)‐pseudo‐meta‐type [2.2]paracyclophanes

A new type of planar chiral (R_p)‐ and (S_p)‐4,7,12,15‐tetrasubstituted [2.2]paracyclophanes was prepared from racemic 4,7,12,15‐tetrabromo[2.2]paracyclophane as the starting substrate. Regioselective lithiation and transformations afforded racemic bis‐(para)‐pseudo‐meta‐type [2.2]paracyclophane (4,15‐dibromo‐7,12‐dihydroxy[2.2]paracyclophane). Its optical resolution was performed by the diastereomer method using a chiral camphanoyl group as the chiral auxiliary. The diastereoisomers were readily isolated by simple silica gel column chromatography, and the successive hydrolysis afforded (R_p)‐ and (S_p)‐bis‐(para)‐pseudo‐meta‐type [2.2]paracyclophanes ((R_p)‐ and (S_p)‐4,15‐dibromo‐7,12‐dihydroxy[2.2]paracyclophanes). They can be used as pseudo‐meta‐substituted chiral building blocks.     

Effects of solvent on inclusion complexation of a chiral dipeptide toward racemic BINOL

The effects of reaction solvent on inclusion complexation of a chiral dipeptide (3S,6S)‐ 1 derived from (S)‐proline toward racemic BINOL was investigated, discovering that the reaction solvent played a crucial role in determining the inclusion complexation behavior of dipeptide (3S,6S)‐ 1 toward rac‐BINOL. (3S,6S)‐ 1 did not show any chiroselective or achiroselective complexation toward rac‐BINOL in polar protic solvents such as methanol and ethanol, polar aprotic solvents including trichloromethane and THF, while in polar aprotic solvent ethyl acetate and apolar aprotic solvents benzene, (3S,6S)‐ 1 displayed achiroselective complexation toward rac‐BINOL. However, the resulting heterocomplex HC‐ 2 from benzene and HC‐ 3 from ethyl acetate have a different composition. Single crystal X‐ray diffraction analysis demonstrates that the two heterocomplexes are formed via different H‐bond interaction patterns, in which the reaction solvent has a dramatic effect. Furthermore, this work provides a relatively green method for quantitative enantiomeric enrichment of nonracemic BINOL, in which unacceptable and toxic benzene was replaced by ethyl acetate.     

Supramolecular chirality transfer in a stereodynamic catalysts

We present rhodium catalysts that contain stereodynamic axially chiral biphenol‐derived phosphinite ligands modified with non‐stereoselective amides for non‐covalent interactions. A chirality transfer was achieved with (R)‐ or (S)‐acetylphenylalanine methyl amide, and the interaction mechanism was investigated by NMR measurements. These interactions at the non‐stereoselective interaction sites and the formation of supramolecular complexes result in an enrichment of either the (R_ax)‐ or (S_ax) enantiomer of the tropos catalysts, which in turn provide the (R)‐ or (S)‐acetylphenylalanine methyl ester in the hydrogenation of (Z)‐methyl‐α‐acetamidocinnamate.     

A Simple Method for Resolution of Endo‐/Exo‐Monoesters of Trans‐Norborn‐5‐Ene‐2,3‐Dicarboxylic Acids Into Their Enantiomers

Separation of optical isomers obtainable from trans‐norborn‐5‐ene‐2,3‐dicarboxylic acid methyl and tert‐butyl monoesters was performed by crystallization of the respective salts prepared with (R)‐ and (S)‐1‐phenylethylamine. Starting from racemic endo‐monomethyl ester of trans‐norborn‐5‐ene‐2,3‐dicarboxylic acid, prepared by partial hydrolysis of the cyclopentadiene‐dimethyl fumarate adduct, the corresponding (2R,3R)‐endo‐monoester was isolated in 97% enantiomeric excess (ee) yield after seven repeated crystallizations from tetrachloromethane. Starting from exo‐mono‐tert‐butyl ester of the same acid, prepared by alcoholysis of the cyclopentadiene‐maleic anhydride adduct followed by isomerization, (2R,3R)‐exo‐monoester was isolated in >98% ee yield after four repeated crystallizations from ethanol. Crystallization of the acids from the mother liquor containing (S)‐1‐phenylethylamine yielded products with inverse stereochemical configuration. Chirality 27:151–155, 2015. © 2014 Wiley Periodicals, Inc.     

Synthesis,chromatographic resolution and chiroptical properties of carboxyibuprofen stereoisomers: Major metabolites of ibuprofen in man

The chromatographic resolution of the four stereoisomers of carboxyibuprofen, a major metabolite of ibuprofen in man, was achieved using a Chiralpak AD chiral stationary phase (CSP) (J.T. Baker, Milton, Keynes, UK). The elution order of the stereoisomers was determined to be 2′S,2R; 2′R,2R; 2′R,2S; 2′S,2S by a combination of stereoselective synthesis of diastereoisomeric mixtures and analysis of the two diastereoisomers isolated from human urine following the administration of (S)-ibuprofen. The individual stereoisomers were isolated by semipreparative chiral phase chromatography and characterized by circular dichroism spectroscopy. Chirality 9:75–87, 1997. © 1997 Wiley-Liss, Inc.     

Introduction of axial chirality in a planar aromatic ligand results in chiral recognition with DNA

Dimerization of a hydroxycarbazole produces an axially chiral biaryl, BICOL ( 2 ). One enantiomer (R)‐ 2 , is capable of enantioselective binding to different polymorphs of DNA. The biaryl (R)‐ 2 was shown by fluorescence and circular dichroism to induce a shift of Z‐DNA to B‐DNA. The opposite enantiomer (S)‐ 2 shows no specific binding. The significant difference in behaviour between the two enantiomers (S)‐ 2 and (R)‐ 2 is in line with molecular modelling studies which show two very different binding geometries between the enantiomers with each polymorph of DNA. Copyright © 2010 John Wiley & Sons, Ltd.     

Experimental and Calculated CPL Spectra and Related Spectroscopic Data of Camphor and Other Simple Chiral Bicyclic Ketones

UV, circular dichroism (CD), fluorescence and circularly polarized luminescence (CPL) spectra were recorded for a set of four related [2.2.1] bicyclic compounds ((1S,4S)‐and (1R,4R)‐1,7,7‐trimethylbicyclo[2.2.1]heptan‐2‐one, namely (1S)‐ and (1R)‐camphor ( 1 ), (1S,4R)‐4,7,7‐trimethylbicyclo[2.2.1]hept‐5‐en‐2‐one, (1S)‐dehydro‐epicamphor ( 2 ), (1S,4S)‐1,7,7‐trimethylbicyclo[2.2.1]heptane‐2,5‐dione, (1S)‐5‐oxocamphor ( 3 ), (1S,4R)‐ and (1R,4S)‐1,7,7‐trimethylbicyclo[2.2.1]heptane‐2,3‐dione, (1S)‐ and (1R)‐camphorquinone ( 4 )) and a set of three related [2.2.2] bicyclic compounds (1S,4S)‐bicyclo[2.2.2]octan‐2,5‐dione (saturated diketone ( 5 )), (1R,4R)‐bicyclo[2.2.2]oct‐7‐en‐2,5‐dione (unsaturated diketone ( 6 )), ((1S,4S)‐bicyclo[2.2.2]oct‐7‐en‐5(S)‐ol‐2‐one (which we refer to as unsaturated hydroxy‐ketone ( 7 )). For the latter three compounds also mid‐IR vibrational circular dichroism (VCD) spectra were recorded and are presented. Time‐Dependent Density Functional (TD‐DFT) calculations provide a satisfactory interpretation of both absorption and emission chiroptical spectra and permit insight into ground and excited state electronic properties. We discuss the applicability of the octant rule or of other approximated models to rationalize the observed sign of the CPL. Chirality 25:589–599, 2013. © 2013 Wiley Periodicals, Inc.     

Double Asymmetric Induction During the Addition of (RP)‐Menthyl Phenyl Phosphine Oxide to Chiral Aldimines

P,C‐Stereogenic α‐amino phosphine oxides were prepared from the addition of (R_P)‐menthyl phenyl phosphine oxide to chiral aldimines under neat condition at 80 °C in up to 91:9 dr_C and 99% yields. The diastereoselectivity was mainly induced by chiral phosphorus that showed matched or mismatched induction with (S)‐ or (R)‐aldimines, respectively. Chirality 28:132–135, 2016. © 2015 Wiley Periodicals, Inc.     

Enantiopure 4‐oxazolin‐2‐ones and 4‐methylene‐2‐oxazolidinones as chiral building blocks in a divergent asymmetric synthesis of heterocycles

Enantiopure 3‐((R)‐ and 3‐((S)‐1‐phenylethyl)‐4‐oxazoline‐2‐ones were evaluated as chiral building blocks for the divergent construction of heterocycles with stereogenic quaternary centers. The N‐(R)‐ or N‐(S)‐1‐phenylethyl group of these compounds proved to be an efficient chiral auxiliary for the asymmetric induction of the 4‐ and 5‐positions of the 4‐oxazolin‐2‐one ring through thermal and MW‐promoted nucleophilic conjugated addition to Michael acceptors and alkyl halides. The resulting adducts were transformed via a cascade process into fused six‐membered carbo‐ and heterocycles. The structure of the reaction products depended on the electrophiles and reaction conditions used. Alternative isomeric 4‐methylene‐2‐oxazolidinones served as chiral precursors for a versatile and divergent approach to highly substituted cyclic carbamates. DFT quantum calculations showed that the formation of bicyclic pyranyl compounds was generated by a diastereoselective concerted hetero‐Diels‐Alder cycloaddition.     

Enantioselective pharmacokinetics of (R)‐ and (S)‐ketamine after a 5‐day infusion in patients with complex regional pain syndrome

Introduction: This study determined the pharmacokinetics and pharmacodynamics of (R)‐ and (S)‐ketamine and (R)‐ and (S)‐norketamine following a 5‐day moderate dose, as a continuous (R,S)‐ketamine infusion in complex regional pain syndrome (CRPS) patients. Materials and methods: Ketamine was titrated to 10–40 mg/h and maintained for 5 days. (R)‐ and (S)‐Ketamine and (R)‐ and (S)‐norketamine pharmacokinetic and pharmacodynamic studies were performed. Blood samples were obtained on Day 1 preinfusion, and at 60–90, 120–150, 180–210, and 240–300 min after the start of the infusion, on Days 2, 3, 4, 5, and on Day 5 at 60 min after the end of infusion. The plasma concentrations of (R)‐ and (S)‐ketamine and (R)‐ and (S)‐norketamine were determined using enantioselective liquid chromatography–mass spectrometry. Results: Ketamine and norketamine levels stabilized 5 h after the start of the infusion. (R)‐Ketamine clearance was significantly lower resulting in higher steady‐state plasma concentrations than (S)‐ketamine. The first‐order elimination for (S)‐norketamine was significantly greater than that of (R)‐enantiomer. When comparing the pharmacokinetic parameters of the patients who responded to ketamine treatment with those who did not, no differences were observed in ketamine clearance and the first‐order elimination of norketamine. Conclusion: The results indicate that (R)‐ and (S)‐ketamine and (R)‐ and (S)‐norketamine plasma concentrations do not explain the antinociceptive activity of the drug in patients suffering from CRPS. Chirality, 2011. © 2010 Wiley‐Liss, Inc.     

Lasiolactols A and B Produced by the Grapevine Fungal Pathogen Lasiodiplodia mediterranea

A strain of Lasiodiplodia mediterranea, a fungus associated with grapevine decline in Sicily, produced several metabolites in liquid medium. Two new dimeric γ‐lactols, lasiolactols A and B ( 1 and 2 ), were characterized as (2S*,3S*,4R*,5R*,2′S*,3′S*,4′R*,5′R*)‐ and (2R*,3S*,4R*,5R*,2′R*,3′S*,4′R*,5′R*)‐(5‐(4‐hydroxymethyl‐3,5‐dimethyl‐tetrahydro‐furan‐2‐yloxy)‐2,4‐dimethyl‐tetrahydro‐furan‐3‐yl]‐methanols by IR, 1D‐ and 2D‐NMR, and HR‐ESI‐MS. Other four metabolites were identified as botryosphaeriodiplodin, (5R)‐5‐hydroxylasiodiplodin, (–)‐(1R,2R)‐jasmonic acid, and (–)‐(3S,4R,5R)‐4‐hydroxymethyl‐3,5‐dimethyldihydro‐2‐furanone ( 3  –  6 , resp.). The absolute configuration (R) at hydroxylated secondary C‐atom C(7) was also established for compound 3 . The compounds 1  –  3 , 5, and 6 , tested for their phytotoxic activities to grapevine cv. Inzolia leaves at different concentrations (0.125, 0.25, 0.5, and 1 mg/ml) were phytotoxic and compound 5 showed the highest toxicity. All metabolites did not show in vitro antifungal activity against four plant pathogens.     

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.     

Single Enantiomer Versus Racemate: Chiral Distinction in the Proton Pump Inhibitors Omeprazole and Esomeprazole

Chiral distinction in the proton pump inhibitor drugs omeprazole and in its chiral‐switch esomeprazole magnesium was studied employing the Density Functional Theory (DFT) method. At B3LYP/6‐311G(d,p), the 6‐methoxy???6‐methoxy and 5‐methoxy???5‐methoxy homochiral and heterochiral dimers were calculated. The chiral distinction free energies (ΔΔG_{298,(RS‐SS)}) between the cyclic C₂‐(S,S)‐ and C_i‐(R,S)‐dimers with two intermolecular hydrogen bonds are 3.8, 1.9 (with BSSE counterpoise correction), and –6.9 (with D3 dispersion and BSSE counterpoise corrections) kJ/mol. Adding water as an implicit solvent (polarized continuum model [PCM] model) resulted in a chiral distinction energy of –3.3 kJ/mol, indicating a reversal of the order of the relative stabilities of C₂‐(S,S)‐ and C_i‐(R,S)‐dimers. The chiral distinction free energies between the corresponding (less stable) C₁‐dimers with one intermolecular hydrogen bond are –9.3, –5.8 (with BSSE CC), 17.6 (D3 + BSSE CC), and –3.2 (H₂O) kJ/mol. The results highlight the contention that omeprazole is not just a superposition of its enantiomer constituents. They are consistent with the pharmacological evidence of enantiomer–enantiomer interactions in omeprazole versus esomeprazole and the differences between the drugs omeprazole and esomeprazole magnesium and support the lodged application for regulatory supplementary protection certificate (SPC) exclusivity for the esomeprazole‐related combination drug Vimovo. Chirality 26:214–227, 2014. © 2014 Wiley Periodicals, 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.     

Enantioselective synthesis and teratogenicity of propylisopropyl acetamide,a CNS‐active chiral amide analogue of valproic acid

Propylisopropyl acetamide (PID), an amide analogue of the major antiepileptic drug valproic acid (VPA), possesses favorable anticonvulsant and CNS properties. PID contains one chiral carbon atom and therefore exists in two enantiomeric forms. The purpose of this work was to synthesize the two PID enantiomers and evaluate their enantiospecific teratogenicity. Enantioselective synthesis of PID enantiomers was achieved by coupling valeroyl chloride with optically pure (4S)‐ and (4R)‐benzyl‐2‐oxazolidinone chiral auxiliaries. The two oxazolidinone enolates were alkylated with isopropyl triflate, hydrolyzed, and amidated to yield (2R)‐ and (2S)‐PID. These two PID enantiomers were obtained with excellent enantiomeric purity, exceeding 99.4%. Unlike VPA, both (2R)‐ and (2S)‐PID failed to exert teratogenic effects in NMRI mice following a single 3 mmol/kg subcutaneous injection. From this study we can conclude that individual PID enantiomers do not demonstrate stereoselective teratogenicity in NMRI mice. Due to its better anticonvulsant activity than VPA and lack of teratogenicity, PID (in a stereospecific or racemic form) has the potential to become a new antiepileptic and CNS drug. Chirality 11:645–650, 1999. © 1999 Wiley‐Liss, Inc.     

Preparation and enantioseparation of a mixed selector chiral stationary phase derived from benzoylated tartaric acid and 1,2‐diphenylethylenediamine

L ‐Dibenzoyl tartaric acid was mono‐esterified with benzyl alcohol, and then chlorinated with SOCl₂ to give (2S,3S)‐1‐(benzyloxy)‐4‐chloro‐1,4‐dioxobutane‐2,3‐diyl dibenzoate (Selector 1 ). (1R,2R)‐1,2‐Diphenylethylenediamine was mono‐functionalized with phenyl isocyanate and phenylene diisocyanate in sequence to give (1R,2R)‐1,2‐diphenyl‐2‐(3‐phenylureido)ethyl 4‐ isocyanatophenylurea (Selector 2 ). Two brush‐type chiral stationary phases (CSPs) of single selector were prepared by separately immobilizing selectors 1 and 2 on aminated silica gel. Selectors 1 and 2 were simultaneously immobilized on aminated silica gel to give a mixed selector CSP. The enantioseparation ability of these CSPs was studied. The CSP of selector 1 has strongest separation ability, while the enantioseparation ability of the mixed selector CSP is relatively lower. Chirality 2010. © 2009 Wiley‐Liss, Inc.     

Configurational studies on red algae carotenoids

The configurations of (6′R)-β,ε-carotene, (3′R,6′R)-β,ε-caroten-3′-ol (α-cryptoxanthin), (3R,3′R,6′R)-β,ε-carotene-3,3′-diol (lutein), (3R)-β,β-caroten-3-ol (β-cryptoxanthin), (3R,3′R)-β,β-carotene-3,3′-diol (zeaxanthin) and all-trans (3S,5R,6S,3′R)-5,6-epoxy-5,6-dihydro-β,β-carotene-3,3′-diol (antheraxanthin) were established by CD and ¹H NMR studies. The red algal carotenoids consequently possessed chiralities at each chiral center (C-3, C-5, C-6, C-3′, C-6′), corresponding to the chiralities established for the same carotenoids in higher plants. Two post mortem artifacts from Erythrotrichia carnea were assigned the chiral structures (3S,5R,8R,3′R)-5,8-epoxy-5,8-dihydro-β,β-carotene-3,3′-diol [(8R)-mutatoxanthin] and (3S,5R,8S,3′R)-5,8-epoxy-5,8-dihydro-β,β-carotene-3,3′-diol [(8S)-mutatoxanthin]. This is the first well documented report of a naturally occurring β,ε-caroten-3′-ol (¹H NMR, CD, chemical derivatization).