High Enantiomeric Excess Research Articles

Asymmetric Diels-Alder Reaction of α,β-Unsaturated Oxazolidin-2-one Derivatives Catalyzed by a Chiral Fe(III)-Bipyridine Diol Complex.

An asymmetric FeIII-bipyridine diol catalyzed Diels-Alder reaction of α,β-unsaturated oxazolidin-2-ones has been developed. Among various FeII/FeIII salts, Fe(ClO4)3·6H2O was selected as the Lewis acid of choice. The use of a low catalyst loading (2 mol % of Fe(ClO4)3·6H2O and 2.4 mol % of Bolm's ligand) afforded high yields (up to 99%) and high enantiomeric excesses (up to 98%) of endo-cycloadducts for the Diels-Alder reaction between cyclopentadiene and substituted acryloyloxazolidin-2-ones. Other noncyclic dienes led to decreased enantioselectivities. A proposed model supports the observed stereoinduction.

Process Development for the Synthesis of Monocyclic β-Lactam Core 17

Process development and multikilogram synthesis of the monocyclic β-lactam core 17 for a novel pyridone-conjugated monobactam antibiotic is described. Starting with commercially available 2-(2,2-diethoxyethyl)isoindoline-1,3-dione, the five-step synthesis features several telescoped operations and direct isolations to provide significant improvement in throughput and reduced solvent usage over initial scale-up campaigns. A particular highlight in this effort includes the development of an efficient Staudinger ketene–imine [2 + 2] cycloaddition reaction of N-Boc-glycine ketene 12 and imine 9 to form racemic β-lactam 13 in good isolated yield (66%) and purity (97%). Another key feature in the synthesis involves a classical resolution of racemic amine 15 to afford single enantiomer salt 17 in excellent isolated yield (45%) with high enantiomeric excess (98%).

Intramolecular Hydrogen Bond Activation: Thiourea-Organocatalyzed Enantioselective 1,3-Dipolar Cycloaddition of Salicylaldehyde-Derived Azomethine Ylides with Nitroalkenes.

An organocatalytic strategy for the synthesis of tetrasubstituted pyrrolidines with monoactivated azomethine ylides in high enantiomeric excess and excellent exo/endo selectivity is presented. The key to success is the intramolecular activation via hydrogen bonding through an o-hydroxy group, which allows the dipolar cycloaddition to take place in the presence of azomethine ylides bearing only one activating group. The intramolecular hydrogen bond in the azomethine ylide and the intermolecular hydrogen bond with the catalyst have been demonstrated by DFT calculations and mechanistic proofs to be crucial for the reaction to proceed.

Microbial Kinetic Resolution of Aroma Compounds Using Solid-State Fermentation

A novel microbial approach to the production of enantiomerically enriched and pure aroma compounds based on kinetic resolution via solid-state fermentation is proposed. Twenty-five filamentous fungi were screened for lipase activity and enantioselective hydrolysis of a volatile racemic ester (1-phenylethyl acetate (1)) and several racemic lactones (trans and cis whisky lactones (4, 5), γ-decalactone (7), δ-decalactone (8), (cis-3a,4,7,7a-tetrahydro-1(3H)-isobenzofuranone) (9)). Solid-state fermentation was conducted with linseed and rapeseed cakes. Kinetic resolution afforded enantiomerically enriched products with high enantiomeric excesses (ee = 82–99%). The results highlight the potential economic value of solid-state fermentation using agroindustrial side-stream feedstocks as an alternative to more expensive processes conducted in submerged fermentation.

Ir-Catalyzed Asymmetric and Regioselective Hydrogenation of Cyclic Allylsilanes and Generation of Quaternary Stereocenters via the Hosomi-Sakurai Allylation.

A number of cyclic dienes containing the allylsilane moiety were prepared by a Birch reduction and subjected to iridium-catalyzed regioselective and asymmetric hydrogenation, which provided chiral allylsilanes in high conversion and enantiomeric excess (up to 99 % ee). The compounds were successively used in the Hosomi-Sakurai allylation with various aldehydes employing TiCl4 as Lewis acid, providing adducts with two additional stereogenic centers in excellent diastereoselectivity.

Two stereocentered HKR of anti-β,β′-diphenylpropanoxirane and anti-3-phenylethyloxiranes catalysed by Co(iii)(salen)-OAc complex: enantioselective synthesis of (+)-sertraline and (+)-naproxen

Two stereocentered HKR of anti-β,β′-diphenylmethyloxirane and anti-3-phenylethyloxiranes gives enantiopure anti-1,2-diols and oxiranes. This method is utilised for the synthesis of (+)-sertraline and (+)-naproxen.

An organocatalytic enantioselective direct α-heteroarylation of aldehydes with isoquinoline N-oxides.

A new protocol for the enantioselective direct α-heteroarylation of aldehydes with isoquinoline N-oxides, via chiral enamine catalysis, has been successfully developed. High enantiomeric excesses and moderate to good yields were achieved for a variety of α-heteroarylated aldehydes.

Deracemization of sec-Alcohols through Sequential Application of C. albicans and Ketoreductases

A biocatalytic cascade process was developed using immobilized cells of the wild type yeast Candida albicans CCT 0776 in calcium alginate beads and a commercially available ketoreductase. The aim was to promote deracemization by stereoinversion of (±)-1-arylethanols in high substrate concentration (above 100 mmol L-1) to prepare the (R)-enantiomers of the alcohols (90-99%), with a high enantiomeric excess (83-99%) after 2 to 19 h. The (R)-1-(3-methoxyphenyl)ethanol, with 70% yield and 91% ee, obtained after 5 h was used to prepare (S)-1-(3-methoxyphenyl)-ethylamine with 60% yield and 91% ee after two steps, a key intermediate in the synthesis of (S)-rivastigmine.

Copper-catalyzed enantioselective 1,2-borylation of 1,3-dienes.

A highly enantioselective Cu-catalyzed borylation of 2-substituted 1,3-dienes is reported. The use of a chiral phosphanamine ligand is essential in achieving high chemo-, regio-, diastereo- and enantioselectivity. It provides access to a variety of homoallylic boronates in consistently high yield and enantiomeric excess with 2-aryl and 2-heteroaryl 1,3-dienes as well as sterically demanding 2-alkyl 1,3-dienes. Preliminary investigations based on a non-linear effect study point to a mechanism involving more than one metal center.

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.

Quinine Thiourea Immobilized on SBA‐15 as an Efficient Recyclable Catalyst for Asymmetric Strecker Reaction of Isatin N‐protected Ketimines

AbstractQuinine thiourea organo‐catalyst immobilized on the SBA‐15 mesoporous material was synthesized by the post‐grafting method. First, the organothiol group was grafted over the SBA‐15 surface and which was anchored with quinine thiourea via. radical polymerization method. The synthesized catalyst was characterized by various physicochemical methods. The 13CP MAS solid‐state NMR confirms the successful grafting of quinine thiourea over the surface of SBA‐15. Thermogravimetric weight loss analysis confirms the successful anchoring of organo‐catalyst. The synthesized organo‐catalyst was used as heterogeneous catalyst for asymmetric Strecker reaction of N‐Boc isatin derived ketimines. The heterogeneous catalyst worked efficiently to give α‐amino nitriles in good yields and high enantiomeric excess up to 93% with 90% conversion in 85 h at –10 °C temperature. Furthermore, the catalyst was successfully reused up to five times without loss in yield and enantioselectivity of the product.

Chemoenzymatic total synthesis of cryptocaryalactone natural products

A new chemoenzymatic route for the preparation of cryptocaryalactones natural products using a kinetic resolution process as the key step is described. Novozyme-435 catalyzed hydrolysis of the prochiral (±)-monoester 7 afforded the precursors of cryptocaryalactones with high enantiomeric excess and excellent yields. The compounds (4S,6S)-7 and (4R,6R)-7 were converted to (+)-(6R,2′S)-cryptocaryalactone (1) and (−)-(6S,2′R)-cryptocaryalactone (2), respectively by employing Wittig-olefination, lactonization and acylation reactions.

Engineered Aminotransferase for the Production of d‐Phenylalanine Derivatives Using Biocatalytic Cascades

Abstractd‐Phenylalanine derivatives are valuable chiral building blocks for a wide range of pharmaceuticals. Here, we developed stereoinversion and deracemization biocatalytic cascades to synthesize d‐phenylalanine derivatives that contain electron‐donating or ‐withdrawing substituents of various sizes and at different positions on the phenyl ring with a high enantiomeric excess (90 to >99 % ee) from commercially available racemic mixtures or l‐amino acids. These whole‐cell systems couple Proteus mirabilis l‐amino acid deaminase with an engineered aminotransferase that displays native‐like activity towards d‐phenylalanine, which we generated from Bacillus sp. YM‐1 d‐amino acid aminotransferase. Our cascades are applicable to preparative‐scale synthesis and do not require cofactor‐regeneration systems or chemical reducing agents.

Iridium-Catalyzed Enantioselective Synthesis of Dihydroimidazoquinazolinones by Elaborate Tuning of Chiral Cyclic Ligands.

A highly efficient, enantioselective intramolecular allylation of (E)-4-(alkyl(4-oxo-3,4-dihydroquinazolin-2-yl)amino)but-2-en-1-yl methyl carbonates was developed, and the corresponding dihydroimidazoquinazolinones were prepared in high yields and enantiomeric excess. The allylation was performed under catalysis of iridium-chiral cyclic phosphoramidite complexes, in which the reactivity and enantioselectivity of the substrates were elaborately tuned by our developed chiral cyclic phosphoramidite ligands with adjustable sizes of rings.

Enantioselective Excited-State Photoreactions Controlled by a Chiral Hydrogen-Bonding Iridium Sensitizer.

Stereochemical control of electronically excited states is a long-standing challenge in photochemical synthesis, and few catalytic systems that produce high enantioselectivities in triplet-state photoreactions are known. We report herein an exceptionally effective chiral photocatalyst that recruits prochiral quinolones using a series of hydrogen-bonding and π-π interactions. The organization of these substrates within the chiral environment of the transition-metal photosensitizer leads to efficient Dexter energy transfer and effective stereoinduction. The relative insensitivity of these organometallic chromophores toward ligand modification enables the optimization of this catalyst structure for high enantiomeric excess at catalyst loadings as much as 100-fold lower than the optimal conditions reported for analogous chiral organic photosensitizers.

Diastereoselective and enantioselective alkaline-hydrolysis of 2-aryl-1-cyclohexyl acetate: a CAL-B catalyzed deacylation/acylation tandem process

Candida antarctica lipase proved to be a particularly efficient lipase for the resolution of racemic 2-arylcyclohexyl acetate in hydrolysis reaction with Na2CO3 in an organic medium. The (1R,2S)-trans-2-arylcyclohexanols 2a–2d were obtained with high ee values (up to >99%) and the selectivity reached E>200. The influence of the enol ester and the solvent on (±)-trans-2-arylcyclohexanol in the CAL-B catalyzed acylation was also studied and compared with the deacylation. The CAL-B exhibits a better affinity for the alkaline hydrolysis reaction compared with acylation with the enol esters in the same organic solvents. The best conditions were applied to resolve a stereoisomeric mixture cis/trans-2-phenyl-1-cyclohexanol and its corresponding acetate by acylation and deacylation. The obtained results show a highly enantio- and diastereoselectivity of the CAL-B during the acylation and the deacylation in favor of the trans-(R)-enantiomer product. The resolution of a mixture of cis/trans-2-arylcyclohexanols was an easy, convenient approach to provide only one stereoisomer of a mixture of four with high enantiomeric excess.

Regioselective Iridium-Catalyzed Asymmetric Monohydrogenation of 1,4-Dienes.

A highly efficient regio- and enantioselective monohydrogenation of 1,4-dienes has been realized using an iridium catalyst with a chiral N,P-ligand under mild conditions. The substrate scope was studied and included both unfunctionalized as well as functionalized substituents on the meta- or para-position. Substrates having substituents with functionalities such as silyl protected alcohols or ketals were monohydrogenated in high regioselectivity and high enantiomeric excess (up to 98% ee).

Total Synthesis of (-)-Rhazinilam and Formal Synthesis of (+)-Eburenine and (+)-Aspidospermidine: Asymmetric Cu-Catalyzed Propargylic Substitution.

A total synthesis of (-)-rhazinilam and formal syntheses of (+)-eburenine and (+)-aspidospermidine that rely on a copper(I)-catalyzed asymmetric propargylic substitution as the key step are reported. A salient feature of the reaction is the asymmetric construction of a quaternary stereocenter in high yield and enantiomeric excess.

Lipase-catalysed two-step desymmetrization of 2-methylmalonic dipyrazolide for preparation of optically pure enantiomer in organic solvents

A lipase-catalysed two-step butanolytic desymmetrization process for the preparation of pyrazolidyl butyl (S)-2-methylmalonate from 2-methylmalonic dipyrazolide was developed. The best reaction condition of using lipase PS-D in anhydrous n-hexane at 55 °C was first selected, leading to high yield and enantiomeric excess for the remained (S)-enantiomer. The kinetic analysis by considering the competitive inhibition from butanol was then carried out for obtaining the stereoselectivity of E1 = 11.2 for the first desymmetrization and enantiomeric ratio of E3E2−1=11.8 for the subsequent kinetic resolution. The thermodynamic analysis furthermore revealed that the enzyme stereodiscrimination was enthalpy-driven for the desymmetrization step, but changed as entropy-driven for the kinetic resolution step.

Persistent organic pollutants in red-crowned cranes (Grus japonensis) from Hokkaido, Japan

The red-crowned crane (Grus japonensis) from eastern Hokkaido is classified as a Special Natural Monument in Japan. In this study, we determined the concentrations of persistent organic pollutants (POPs) in red-crowned crane muscle tissues (n = 47). Polychlorinated biphenyls (PCBs) had the highest median concentration (240ng/g lipid weight), followed by dichlorodiphenyltrichloroethane and its metabolites (DDTs) (150ng/g lipid weight), chlordane-related compounds (CHLs) (36ng/g lipid weight), hexachlorobenzene (HCB) (16ng/g lipid weight), hexachlorocyclohexanes (HCHs) (4.4ng/g lipid weight), polybrominated diphenyl ethers (PBDEs) (1.8ng/g lipid weight), and finally, Mirex (1.5ng/g lipid weight). Additionally, a positive correlation was found among POP concentrations. No sex differences beyond body parameters were observed. Additionally, red-crowned cranes exhibited a high enantiomeric excess of (+)-alpha-HCH, with enantiomer fractions varying from 0.51 to 0.87 (average: 0.69).