High Enantiomeric Purity Research Articles

Radiosynthesis and modified quality control of O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) for brain tumor imaging

O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) is the most promising radio-labeled amino acid tracer for brain tumor imaging due to the limitation of 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) and L-methyl-[11C]methionine (11C-MET). However, it has some limitations in radiosynthesis and related quality control that make it less frequently used in many PET centers, in this study, we report a new modification of [18F]FET production using a commercially available fully automated GRP SCINTOMICS module overcoming some of the existing limitations along with a suggestion of a simplified quality control procedure with special focus placed on enantiomeric and radiochemical purity. ([18F]FET) was produced in high radiochemical and enantiomeric purity more than 99% and non-decay corrected yield 25±5% in about 55min.

Enantiospecific Synthesis of Imidazoquinazolin-2-ones via Base-Catalyzed Tandem Cyclization

A facile protocol for the enantiospecific synthesis of novel (S)-3-substituted imidazo[2, l-b]quinazoline-2-ones via tandem reaction of substituted (S)-3-amino-4-aminomethylbenzoates and cyanogen bromide under basic conditions is explored. This tandem process involves addition reaction of substituted (S)-3-amino-4-aminomethylbenzoates to CNBr to yield 2-imino tetrahydroquinazoline carboxylate intermediates followed by in situ intramolecular aminolysis to afford the triheterocyclic imidazo[2, l-b]quinazoline-2-ones in good yields and high enantiomeric purity.

Enantioselective Direct Mannich‐Type Reactions Catalyzed by Frustrated Lewis Acid/Brønsted Base Complexes

AbstractAn enantioselective direct Mannich‐type reaction catalyzed by a sterically frustrated Lewis acid/Brønsted base complex is disclosed. Cooperative functioning of the chiral Lewis acid and achiral Brønsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen‐bond‐activated aldimines delivers β‐aminocarbonyl compounds with high enantiomeric purity.

Enantioselective Direct Mannich-Type Reactions Catalyzed by Frustrated Lewis Acid/Brønsted Base Complexes.

An enantioselective direct Mannich-type reaction catalyzed by a sterically frustrated Lewis acid/Brønsted base complex is disclosed. Cooperative functioning of the chiral Lewis acid and achiral Brønsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen-bond-activated aldimines delivers β-aminocarbonyl compounds with high enantiomeric purity.

Purification of biomevalonate from fermentation broth and conversion of biomevalonate into biomevalonolactone

Mevalonate (MVA) is a key compound of living organisms including bacteria, plants, and humans. MVA and mevalonolactone (MVL), a lactonized form of MVA, are important for pharmaceutical, cosmeceutical, and biotechnological applications. Although (R, S)-MVA with 50% enantiomeric purity is mainly produced by chemical synthesis, recently, microbial fermentation processes for MVA production have been considered as an alternative to the chemical synthesis because of high enantiomeric purity [(R)-MVA] and high titer. In the present study, bio-MVA produced by a fermentative process was decolorized by a charcoal-based method and then chemically transformed into bio-MVL without byproducts by means of phosphoric acid as an acid catalyst. The final bio-MVL was (R)-MVL with over 99% enantiomeric purity according to 1H NMR analysis.

Sceptrin – Enantioselective Synthesis of a Tetrasubstituted all‐trans Cyclobutane Key Intermediate

The asymmetric synthesis of both enantiomers of tetrasubstituted all‐trans dimethyl 3,4‐diacetylcyclobutane‐1,2‐dicarboxylate with high enantiomeric purity (>98 % ee) using a valine‐derived chiral auxiliary in a diastereoselective photodimerization is reported. The absolute configuration was assigned by single‐crystal X‐ray diffraction analysis. Because this cyclobutane is a key intermediate in the total synthesis of (–)‐sceptrin and ageliferin, our findings strengthen the recently revised absolute configurations of these pyrrole‐imidazole alkaloids.

Total Synthesis of Bruceolline I.

The first total synthesis of the natural product bruceolline I, isolated in small quantities from the ethanol extract of Brucea mollis stems, was achieved in 29% yield over nine steps and with high enantiomeric purity (>98%). The key step of the process is the tandem gold-catalyzed rearrangement/Nazarov reaction of a propargylic acetate derivative. This synthesis provides a sufficient amount of synthesized bruceolline I for further bioassays.

Pharmacokinetic Characterization of [18F]UCB-H PET Radiopharmaceutical in the Rat Brain.

The synaptic vesicle glycoprotein 2A (SV2A), a protein essential to the proper nervous system function, is found in presynaptic vesicles. Thus, SV2A targeting, using dedicated radiotracers combined with positron emission tomography (PET), allows the assessment of synaptic density in the living brain. The first-in-class fluorinated SV2A specific radioligand, [18F]UCB-H, is now available at high activity through an efficient radiosynthesis compliant with current good manufacturing practices (cGMP). We report here a noninvasive method to quantify [18F]UCB-H binding in rat brain with microPET. Validation study in rats confirmed the need of high enantiomeric purity to target SV2A in vivo. We demonstrated the reliability of a population-based input function to quantify SV2A in preclinical microPET setting. Finally, we investigated the in vivo metabolism of [18F]UCB-H and confirmed the negligible amount of radiometabolites in the rat brain. Hence, the in vivo quantification of SV2A using [18F]UCB-H microPET seems a promising tool for the assessment of the synaptic density in the rat brain, and opens the way for longitudinal follow-up in neurodegenerative disease rodent models.

Copper-Catalyzed Asymmetric Hydroboration of 1,1-Disubstituted Alkenes.

A mild and efficient approach for highly regio- and enantioselective copper-catalyzed hydroboration of 1,1-diaryl substituted alkenes with bis(pinacolato)diboron (B2Pin2) was developed for the first time, providing facile access to a series of valuable β,β-diaryl substituted boronic esters with high enantiomeric purity. Moreover, this approach could also be suitable for hydroboration of α-alkyl styrenes for the synthesis of enantioenriched β,β-arylalkyl substituted boronic esters. Gram-scale reaction, stereospecific derivatizations, and the application of important antimuscarinic drug (R)-tolterodine for concise enantioselective synthesis further highlighted the attractiveness of this new approach.

Enantioselective Synthesis of Isoflavanones by Catalytic Dynamic Kinetic Resolution.

A ruthenium-catalyzed asymmetric transfer hydrogenation of racemic isoflavanones with dynamic kinetic resolution yields virtually enantiopure isoflavanols as single diastereomers. Subsequent oxidation gives rise to isoflavanones in high enantiomeric purities.

Stereoselective Construction of Entire Diastereomeric Stereotetrads Based on an Asymmetric Morita–Baylis–Hillman Reaction

A method for the enantio‐ and diastereoselective construction of all possible stereoisomers of a polypropionate stereotetrad having four contiguous stereogenic centers has been developed. The approach features an iterative sequence of cinchona‐alkaloid‐catalyzed Morita–Baylis–Hillman reaction and subsequent diastereoselective hydrogenation. By this method, benzaldehyde was successfully converted into eight diastereoisomeric 3,5‐dihydroxy‐2,4‐dimethyl‐5‐phenylpentanoic acid ester derivatives with high enantiomeric purities (99 % ee) in 25–67 % overall yield (eight steps) in a reagent‐controlled manner.

Design and Development of Highly Potent HIV-1 Protease Inhibitors with a Crown-Like Oxotricyclic Core as the P2-Ligand To Combat Multidrug-Resistant HIV Variants.

Design, synthesis, and evaluation of a new class of exceptionally potent HIV-1 protease inhibitors are reported. Inhibitor 5 displayed superior antiviral activity and drug-resistance profiles. In fact, this inhibitor showed several orders of magnitude improved antiviral activity over the FDA approved drug darunavir. This inhibitor incorporates an unprecedented 6-5-5 ring-fused crown-like tetrahydropyranofuran as the P2 ligand and an aminobenzothiazole as the P2' ligand with the (R)-hydroxyethylsulfonamide isostere. The crown-like P2 ligand for this inhibitor has been synthesized efficiently in an optically active form using a chiral Diels-Alder catalyst providing a key intermediate in high enantiomeric purity. Two high resolution X-ray structures of inhibitor-bound HIV-1 protease revealed extensive interactions with the backbone atoms of HIV-1 protease and provided molecular insight into the binding properties of these new inhibitors.

Intramolecular vinylation of carbanions using N-acyl benzomorpholines as masked vinylureas and vinylcarbamates

Treatment of urea or carbamate derived benzomorpholines with lithium diisopropylamide generates N -vinyl ureas or N -vinyl carbamates by elimination of a phenoxide anion, cleaving the benzomorpholine ring. Simultaneous formation of a carbanion α to a stabilising aryl or nitrile group allows migration of the newly formed N -vinyl substituent to the carbanionic centre, in some cases with high enantiospecificity. Mild hydrolysis of the resulting urea or carbamate returns a C -vinylated amine, alcohol or hydantoin, in some cases with high enantiomeric purity. This ‘masked’ vinylation strategy avoids the need to use the reactive and volatile vinyl isocyanate as a starting material.

Stereoselective Copper-Catalyzed Cross-Coupling of Aziridines with Benzimidazoles via Nucleophilic Ring Opening and C(sp2)-H Functionalization.

A copper-catalyzed cross-coupling of 2-alkyl-/2-arylaziridines with benzimidazoles is reported. The reactions involve a regiospecific ring opening of aziridines with benzimidazoles to give benzoimidazolylethylamine derivatives that lead to dehydrogenative cross-coupling between C(sp2)-H and N-H bonds to produce dihydroimidazobenzimidazoles. Optically active 2-arylaziridines can be stereoinvertivebly cross-coupled with high enantiomeric purities (77-97% ee). These aerobic catalytic systems comprise an inexpensive Cu(II) salt and PCy3 ligand at moderate temperature.

Enantioselective Resolution of (R,S)-Carvedilol to (S)-(\u2212)-Carvedilol by Biocatalysts

Among the microorganisms employed in the study, Aspergillus niger (GUFCC5443), Escherichia coli (ATCC9637), Streptomyces halstedii (CKM-2), Pseudomonas putida (NCIB9494), Cunninghamella elegans (NCIM689) and Sphingomonas paucimobilis (NCTC11030) were capable for the enantioselective conversion of racemic Carvedilol. Immobilization technique enhanced the enantioselectivity of microorganisms and thus increased the enantiomeric purity of the drug. Excellent enantiomeric ratios (E) were found in reactions catalyzed by immobilized A. niger and E. coli with values 174.44 and 104.26, respectively. Triacylglycerol lipase from Aspergillus niger was also employed in this study as a biocatalyst which resulted in the product with 83.35% enantiomeric excess (ee) and E of 11.34 while the enzyme on immobilization has yielded 99.08% ee and 216.39 E. The conversion yield (C%) of the drug by free-enzyme was 57.42%, which was enhanced by immobilization to 90.51%. Hence, our results suggest that immobilized triacylglycerol lipase from A. niger (Lipase AP6) could be an efficient biocatalyst for the enantioselective resolution of racemic Carvedilol to (S)-(−)-Carvedilol with high enantiomeric purity followed by immobilized cultures of A. niger and E. coli.

Enantioselective γ-borylation of unsaturated amides and stereoretentive Suzuki-Miyaura cross-coupling.

The rhodium-catalyzed, directed catalytic asymmetric hydroboration of γ,δ-unsaturated amides affords a direct route to chiral acyclic secondary γ-borylated carbonyl derivatives in high enantiomeric purity. In contrast to a similar β-borylated amide derivative, the γ-borylated amide undergoes Suzuki-Miyaura cross-coupling with stereoretention. The utility of the boronic ester products is further illustrated by other stereospecific C-B bond transformations leading to γ-amino acid derivatives, 1,4-amino alcohols, and 5-substituted-γ-lactone and γ-lactam ring systems.

Frustrated Lewis Acid/Brønsted Base Catalysts for Direct Enantioselective α-Amination of Carbonyl Compounds.

A method for enantioselective direct α-amination reaction catalyzed by a sterically "frustrated" Lewis acid/Brønsted base complex is disclosed. Cooperative functioning of the Lewis acid and Brønsted base components gives rise to in situ enolate generation from monocarbonyl compounds. Subsequent reaction with hydrogen-bond activated dialkyl azodicarboxylates delivers α-aminocarbonyl compounds in high enantiomeric purity.

Aggregation-driven, re-entrant isotropic phase in a smectic liquid crystal material

ABSTRACTAn azobenzene-core chiral mesogen designed for a photoactive ferroelectric liquid crystal system with switchable polarisation displays a highly unusual phase sequence, with a re-entrant, optically isotropic, fluid phase found below smectic phases in mixtures with high enantiomeric purity. The re-entrant isotropic phase is found on the basis of X-ray scattering and freeze-fracture transmission electron microscopy experiments not to be a cubic or other highly ordered phase but instead a translationally disordered liquid. The material also forms a gel under a wide range of concentrations in 50:50 ethanol/chloroform solutions. Ultraviolet/visible and infrared spectroscopy and quantum chemistry calculations suggest that the primary unit in the re-entrant isotropic and gel phases is a dimer composed of molecules crossed by about 90°, which hinders the formation of crystal phases and forms tubules of helical aggregates in the gel phase.

Model-Based Analysis of Continuous Crystallization/Reaction Processes Separating Conglomerate Forming Enantiomers

The separation of conglomerate forming chiral molecules is investigated in continuous processes combining crystallization, milling, and a racemization reaction in solution. Two process configurations that increase enantiomeric purity starting from racemic mixtures are presented and assessed with respect to attainable enantiopurities, achievable yields, and productivities. The two processes differ in their feeding strategy: one is fed with a supersaturated solution of racemic composition, and one is fed with a racemic mixture of solids. The two cases are studied using a consistent mathematical model based on population balance equations. A parameteric analysis on the key operating parameters of the processes is conducted, and operating regions leading to high enantiomeric purity are identified. By combining the crystallization/mill/reaction process with appropriate filtration and solvent removal units, as well as recycle operations, we show that full enantiomeric purity at 100% yield is theoretically attai...

ChemInform Abstract: Kinetic Resolution of Benzylamines via Palladium(II)‐Catalyzed C—H Cross‐Coupling.

A Pd(II)-catalyzed enantioselective C–H cross-coupling of benzylamines via kinetic resolution has been achieved using chiral mono-N-protected α-amino-O-methylhydroxamic acid (MPAHA) ligands. Both chiral benzylamines and ortho-arylated benzylamines are obtained in high enantiomeric purity. The use of a readily removable nosyl (Ns) protected amino group as the directing group is a crucial practical advantage. Moreover, the ortho-arylated benzylamine products could be further transformed into chiral 6-substituted 5,6-dihydrophenanthridines as important structural motifs in natural products and bioactive molecules.