High Enantiomeric Purity Research Articles

Diastereoselective α-Fluorination of N- tert-Butanesulfinyl Imidates.

A diastereoselective α-fluorination of N- tert-butanesulfinyl imidates was developed. Deprotonation of N- tert-butanesulfinyl imidates with lithium hexamethyldisilazide generates aza-enolates that can be intercepted, with excellent diastereocontrol, by the inexpensive electrophilic fluorinating agent NFSI. This protocol was applied to the preparation of synthetically useful trans-2-fluoro-cyclohexamine with high enantiomeric purity (99.5% ee).

NHC-Copper-Catalyzed Asymmetric Dearomative Silylation of Indoles.

We report an asymmetric dearomative silylation reaction of 3-acylindoles using a chiral NHC-copper(I) complex as catalyst to afford a range of cyclic α-aminosilanes with high regio- and enantioselectivity. Initial mechanistic studies revealed that the observed high diastereoselectivity was attributed to the facile epimerization of the 3-acyl group. We also demonstrated that the product could be used as a versatile precursor for the synthesis of functionalized indolines in high enantiomeric purity.

Cu-catalyzed Asymmetric Dearomative [3 + 2] Cycloaddition Reaction of Benzazoles with Aminocyclopropanes

Summary Heterocycles are a very important class of compounds that exist extensively as structural cores in natural products and biologically active molecules. Catalytic asymmetric dearomatization (CADA) is an efficient strategy for the construction of chiral fused- or spiro-heterocycles from simple planar aromatic compounds. Herein, we report the development of enantioselective dearomative [3 + 2] cycloaddition reactions of benzazoles with aminocyclopropanes via kinetic resolution. In the presence of a copper complex, derived from Cu(OTf)2 and bisoxazoline, a series of hydropyrrolo-benzazole derivatives containing quaternary stereogenic centers were obtained in high yields (up to 99%) with excellent enantioselectivity (up to 99% enantiomeric excess [ee]). With the same catalytic system, 2-amino cyclopropane-1,1-dicarboxylates with a high enantiomeric purity (up to 98% ee) were also obtained by an efficient kinetic resolution (s values of up to 95). In addition, the utility of this method was showcased by the facile transformation of products into several important heterocyclic frameworks, including pyrrolo-benzothiazine and 1,5-benzothiazepine.

Bifunctional Amine-Squaramides as Organocatalysts in Michael/Hemiketalization Reactions of β,γ-Unsaturated α-Ketoesters and α,β-Unsaturated Ketones with 4-Hydroxycoumarins.

The catalytic efficiency of various amine-squaramides was tested in Michael/hemiketalization reactions of 4-hydroxycoumarines with two types of enones. Tertiary amine-squaramide organocatalysts afforded the best results regarding both activity and enantioselectivity when β,γ-unsaturated α-ketoesters were used as the Michael acceptors (yields up to 98%, enantioselectivities up to 90% ee). On the other hand, the primary amine-squaramides are the best choice for related reactions of 4-hydroxycoumarins with enones. The corresponding pyrano[3,2- c]chromen-5-on products were obtained in high enantiomeric purities (up to 96%). The Michael addition of 4-hydroxycoumarin to 4-phenylbut-3-en-2-on directly produced chiral anticoagulant drug ( S)-warfarin in 92% ee when green solvent 2-MeTHF and catalyst ( S, S)-C8 were used. Moreover, an enantiomeric catalyst ( R, R)-C8 gave ( R)-warfarin in >99% ee.

PEG600-carboxylates as acylating agents for the continuous enzymatic kinetic resolution of alcohols and amines

Enantiomerically pure alcohols and amines are important building blocks for the pharmaceutical and agrochemical industries. Among the different approaches to reach these compounds, enzyme-catalyzed kinetic resolution (EKR) of racemates is one of the most widely studied and employed methodologies. In this kind of reaction, the acyl donor plays an important role, making the search for new acylating agents an attractive field. Herein, we report our results over the use of PEG600 carboxylates as acylating agent for separation of amines and alcohols enantiomers in continuous flow. For the EKR of 1-phenylethylamine, PEG600-diester show the best results, and (S)-1-phenylethylamine was obtained with high yield and enantiomeric purity (49% yield and >99% (S)) with a productivity of 211 mg h−1 genzyme−1. (R)-1-phenylethylamine was recovered after chemical hydrolysis of the amide formed with high yield and ee (35% yield and 95% ee). In addition, the immobilized enzyme remains active for at least 20 h operation. On the other hand, (R)- and (S)-1-phenylethanol was obtained after continuous lipase-catalyzed hydrolysis of the ester (formed after reaction with PEG) in good conversions to both enantiomers, with a productivity of 68 mg h−1 g enzyme−1 for the (S)- enantiomer and 64 mg h−1 genzyme−1 for the (R) enantiomer.

Diastereocontrolled Monoprotodeboronation of β‐Sulfinimido gem‐Bis(boronates): A General and Stereoselective Route to α,β‐Disubstituted β‐Aminoalkylboronates

Abstractβ‐Aminoalkylboronic acids are bioisosteres of the pharmaceutically important class of β‐amino acids but few stereoselective methods exist for their preparation. The 1,2‐addition of lithiated 1,1‐diborylalkanes onto chiral N‐tert‐butanesulfinyl aldimines produces β‐sulfinimido gem‐bis(boronates) in good to excellent yields with high diastereoselectivity. The optimized conditions involve the use of rubidium fluoride and water, and are compatible with functionalized alkyl, aryl, alkenyl, and alkynyl substituents. Under these conditions, the geminal quaternary alkyl bis(pinacolatoboryl) intermediates undergo a highly diastereoselective monoprotodeboronation to afford a wide range of syn‐α,β‐disubstituted β‐aminoalkylboronates. This novel application of protodeboronation chemistry was shown to result from a kinetically controlled, diastereotopic‐group‐selective B−C bond protolysis dictated by the configuration of the adjacent stereogenic C−N center. Facile acidic cleavage of the sulfinimide auxiliary produces the free aminoboronates with high enantiomeric purity.

Diastereocontrolled Monoprotodeboronation of β-Sulfinimido gem-Bis(boronates): A General and Stereoselective Route to α,β-Disubstituted β-Aminoalkylboronates.

β-Aminoalkylboronic acids are bioisosteres of the pharmaceutically important class of β-amino acids but few stereoselective methods exist for their preparation. The 1,2-addition of lithiated 1,1-diborylalkanes onto chiral N-tert-butanesulfinyl aldimines produces β-sulfinimido gem-bis(boronates) in good to excellent yields with high diastereoselectivity. The optimized conditions involve the use of rubidium fluoride and water, and are compatible with functionalized alkyl, aryl, alkenyl, and alkynyl substituents. Under these conditions, the geminal quaternary alkyl bis(pinacolatoboryl) intermediates undergo a highly diastereoselective monoprotodeboronation to afford a wide range of syn-α,β-disubstituted β-aminoalkylboronates. This novel application of protodeboronation chemistry was shown to result from a kinetically controlled, diastereotopic-group-selective B-C bond protolysis dictated by the configuration of the adjacent stereogenic C-N center. Facile acidic cleavage of the sulfinimide auxiliary produces the free aminoboronates with high enantiomeric purity.

Stereospecific Ring Opening and Cycloisomerization of Aziridines with Propargylamines: Synthesis of Functionalized Piperazines and Tetrahydropyrazines.

Stereospecific Cu-catalyzed nucleophilic ring opening of N-sulfonylaziridines with propargylamines and subsequent hydroamination afford piperazines, which leads to double-bond isomerization to furnish tetrahydropyrazines. Optically active aziridines can be cross-coupled with high enantiomeric purities (>98% ee).

Synthesis and Pharmacological Evaluation of Enantiomerically Pure GluN2B Selective NMDA Receptor Antagonists.

To determine the eutomers of potent GluN2B-selective N-methyl-d-aspartate (NMDA) receptor antagonists with a 3-benzazepine scaffold, 7-benzyloxy-3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepin-1-ols (S)-2 and (R)-2 were separated by chiral HPLC. Hydrogenolysis and subsequent methylation of the enantiomerically pure benzyl ethers of (S)-2 and (R)-2 provided the enantiomeric phenols (S)-3 and (R)-3 [3-(4-phenylbutyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1,7-diol] and methyl ethers (S)-4 and (R)-4. All enantiomers were obtained with high enantiomeric purity (≥99.7 % ee). The absolute configurations were determined by CD spectroscopy. R-configured enantiomers turned out to be the eutomers in receptor binding studies and two-electrode voltage clamp experiments. The most promising ligand of this compound series is the R-configured phenol (R)-3, displaying high GluN2B affinity (Ki =30 nm), high inhibition of ion flux (IC50 =61 nm), and high cytoprotective activity (IC50 =93 nm). Whereas the eudismic ratio in the receptor binding assay is 25, the eudismic ratio in the electrophysiological experiment is 3.

Crystallization of Chiral para-n-Alkylphenyl Glycerol Ethers: Phase Diversity and Impressive Predominance of Homochiral Guaifenesin-Like Supramolecular Motif

When studying the crystallization in a monotonously varying series of chiral glycerol ethers para-Alk-C6H4-OCH2CH(OH)CH2OH [Alk = Me (1), Et (2), n-Pr (3), and n-Bu (4)] it was established that all except one member form stable crystalline homo- or heterochiral α-phase, depending on the enantiomeric composition (racemic or close to enantiopure) of the feed medium. Propyl derivative 3 falls out of the series and invariably forms stable homochiral crystals. Regardless of the enantiomeric composition, the last two members of the set can form a stable (4) or metastable (3) liquid-crystalline β-phase. For the entire set, regardless of enantiomeric composition, the formation of metastable γ-phase was registered in supercooled melts; according to a number of evidence, the phase is close to an ideal solid solution of enantiomers. It is shown by X-ray diffraction analysis that in crystals of 1–4 samples with high enantiomeric purity, as well as in racemic 3 and 4 samples, a common homochiral guaifenesin-like supra...

Asymmetric synthesis and structure-activity studies of the fungal metabolites colletorin A, colletochlorin A and their halogenates analogues

The first asymmetric total synthesis of both enantiomers of the natural products colletorin A and colletochlorin A is presented. The proposed methodology is based on the coupling reaction between highly substituted aromatic Gilman cuprates and optically active allyl bromides, in turn obtained by Sharpless asymmetric dihydroxylation. The latter ensured a high degree of regio- and stereocontrol in the enantioselective step of the synthesis. The same synthetic strategy has been also applied for the preparation of differently halogenated synthetic analogues of colletochlorin A in high enantiomeric purity. The enantioselective synthesis of colletorin A and colletochlorin A allows to reliably assign their absolute configuration. Preliminary assessment of their herbicidal and insecticidal properties evidence the possibility to modulate the bioactivity of these compounds, highlighting its dependence on both the absolute stereochemistry and the halogen nature.

Switchable Synthesis of Z-Homoallylic Boronates and E-Allylic Boronates by Enantioselective Copper-Catalyzed 1,6-Boration.

The enantioselective Cu-catalyzed 1,6-boration of (E,E)-α,β,γ,δ-unsaturated ketones is described, which gives homoallylic boronates with high enantiomeric purity and unexpectedly high Z-selectivity. By changing the solvent, the outcome can be altered to give E-allylic boronates.

Highly Efficient Deracemization of Racemic 2-Hydroxy Acids in a Three-Enzyme Co-Expression System Using a Novel Ketoacid Reductase.

Enantiopure 2-hydroxy acids (2-HAs) are important intermediates for the synthesis of pharmaceuticals and fine chemicals. Deracemization of racemic 2-HAs into the corresponding single enantiomers represents an economical and highly efficient approach for synthesizing chiral 2-HAs in industry. In this work, a novel ketoacid reductase from Leuconostoc lactis (LlKAR) with higher activity and substrate tolerance towards aromatic α-ketoacids was discovered by genome mining, and then its enzymatic properties were characterized. Accordingly, an engineered Escherichia coli (HADH-LlKAR-GDH) co-expressing 2-hydroxyacid dehydrogenase, LlKAR, and glucose dehydrogenase was constructed for efficient deracemization of racemic 2-HAs. Most of the racemic 2-HAs were deracemized to their (R)-isomers at high yields and enantiomeric purity. In the case of racemic 2-chloromandelic acid, as much as 300mM of substrate was completely transformed into the optically pure (R)-2-chloromandelic acid (> 99% enantiomeric excess) with a high productivity of 83.8gL-1day-1 without addition of exogenous cofactor, which make this novel whole-cell biocatalyst more promising and competitive in practical application.

Preparation of Optically Enriched Secondary Alkyllithium and Alkylcopper Reagents-Synthesis of (-)-Lardolure and Siphonarienal.

Optically enriched secondary alkyl iodides were converted into secondary alkyllithium and secondary alkylcopper compounds with very high retention of configuration. Quenching with various electrophiles, including chiral epoxides, provided a range of chiral molecules with high enantiomeric purity (>90 % ee). This method has been applied in an iterative fashion in the total synthesis of (-)-lardolure in 13 steps and 5.4 % overall yield (>99 % ee, dr>99:1) and siphonarienal in 15 steps and 5.6 % overall yield (>99 % ee, dr>99:1) starting from commercially available ethyl (R)-3-hydroxybutyrate (>99 % ee).

Use of Lactobacillus rhamnosus (ATCC 53103) as Whole-Cell Biocatalyst for the Regio- and Stereoselective Hydration of Oleic, Linoleic, and Linolenic Acid

Natural hydroxy fatty acids are relevant starting materials for the production of a number of industrial fine chemicals, such as different high-value flavour ingredients. Only a few of the latter hydroxy acid derivatives are available on a large scale. Therefore, their preparation by microbial hydration of unsaturated fatty acids, affordable from vegetable oils, is a new biotechnological challenge. In this study, we describe the use of the probiotic bacterium Lactobacillus rhamnosus (ATCC 53103) as whole-cell biocatalyst for the hydration of the most common unsaturated octadecanoic acids, namely oleic acid, linoleic acid, and linolenic acid. We discovered that the addition of the latter fatty acids to an anaerobic colture of the latter strain, during the early stage of its exponential growth, allows the production of the corresponding mono-hydroxy derivatives. In these experimental conditions, the hydration reaction proceeds with high regio- and stereoselectivity. Only 10-hydroxy derivatives were formed and the resulting (R)-10-hydroxystearic acid, (S)-(12Z)-10-hydroxy-octadecenoic acid, and (S)-(12Z,15Z)-10-hydroxy-octadecadienoic acid were obtained in very high enantiomeric purity (ee > 95%). Although overall conversions usually do not exceed 50% yield, our biotransformation protocol is stereoselective, scalable, and holds preparative significance.

Synthesis of optically pure ant pheromones with high enantiomeric purity.

Chemical ecology studies with insects have founded that pheromonal communications often includes several components which can be linear, cyclic or heterocyclic compounds, in the case of chiral pheromones, insect often show the ability to characterize between and respond differently to stereoisomer. Among the most notable are those cases in which differential interspecific responses to enantiomer serve as a species isolating mechanism, the relationship between stereoisomers and pheromone activity are highly specific, meaningful assays and evaluation of the responses of insect to chiral pheromones must be carried out using substances of the highest possible chiral purity, we prepare ant pheromones using poly methyl methacrylate as chiral auxiliaries with high enantiomeric purity and the prepared compounds were characterized with spectroscopic data and the diastereomeric amides were separated using high performance liquid chromatography and give high enantiomeric excess, also we study the biological applications of our products and give agood results.

Enantioselective Conversion of Racemic Sotalol to R(-)-Sotalol by Lipase AP6

This study was aimed at selecting suitable biocatalysts for the enantioselective conversion of racemic sotalol to R(-)-sotalol and to determine the effect of immobilization on enantiomeric purity of the product. Among the various biocatalysts used, Aspergillus niger (GUFCC5443), Cunninghamella blakesleeana (CBS133.27), Cunninghamella elegans (NCIM689), Pseudomonas putida (NCIB9494), Rhodococcus erythropolis (DSM43188), Rhizopus oryzae (NCIM1009), the enzyme lipase AP6 (triacylglycerol lipase from A. niger) demonstrated the capability for enantioselective conversion. Enantioselectivity of all the cultures was improved by immobilization, which resulted in enhanced enantiomeric purity of the product. Catalysis studies with immobilized R. erythropolis and A. niger cultures yielded good enantiomeric ratios of 55.87 and 53.34 as well as good enantiomeric excesses as 96.48 and 96.45 %, respectively. Catalysis with free lipase AP6 resulted in a product of good enantiomeric purity. This enzyme’s enantioselectivity was improved by immobilization from 11.51 to 168.49, which resulted in a product with very high enantiomeric purity of 98.82 %. Hence, the immobilized-lipase AP6 was proved to be an efficient catalyst for the enantioselective conversion of racemic sotalol to R(-)-sotalol with high enantiomeric purity followed by immobilized R. erythropolis and A. niger.

Expedient stereospecific Co-catalyzed tandem C-N and C-O bond formation of N-methylanilines with styrene oxides.

Cobalt(ii)-catalyzed stereospecific coupling of N-methylanilines with styrene oxides is developed via tandem C-N and C-O bond formation using tert-butyl hydroperoxide (TBHP) as an oxidant. Optically active epoxide can be reacted with high optical purity.

A highly efficient one-enzyme protocol using ω-transaminase and an amino donor enabling equilibrium displacement assisted by molecular oxygen

A highly efficient one-enzyme procedure using ω-transaminase promoted by molecular oxygen for preparing high enantiomeric purity chiral amines was described.

Stereodivergent Syntheses of altro and manno Stereoisomers of 2‐Acetamido‐1,2‐dideoxynojirimycin

A stereoselective synthesis of 2‐acetamido‐1,2‐dideoxyaltronojirimycin (8) and its manno epimer 9 is described. The synthetic approach is based on key bicyclic carbamate 7, which is easily accessible with high enantiomeric purity on a multigram scale by Sharpless asymmetric epoxidation of 1,4‐pentadien‐3‐ol or 2,4‐pentadien‐1‐ol. This procedure completes an efficient stereodivergent approach to five isomers of 2‐acetamido‐1,2‐dideoxyiminosugars in high overall yields starting from the same key intermediate 7. The approach described in this paper is based on control of the stereoselectivity of the sulfite ring‐opening reaction to give retention of configuration through anchimeric assistance from the endocyclic amine.