Axially dissymmetric (R)-(+)-5,5',6,6',7,7',8,8' octahydro-[1,1']binaphthyldiimine chiral salen type-ligands for copper-catalyzed asymmetric aziridination

Axially dissymmetric chiral diimine ligand 2 was prepared from the reaction of (R)-(+)-5,5',6,6',7,7',8,8'-octahydro-[1,1']binaphthyl-2,2'-diamine 1 with 2,6-dichlorobenzaldehyde. The catalytic asymmetric aziridination of alkenes was examined using this novel chiral ligand. Excellent enantioselective aziridination of cinnamates was achieved using C(2)-symmetric chiral ligand 2.     

Asymmetric total synthesis of (+)- and (-)-clusianone and (+)- and (-)-clusianone methyl enol ether via ACC alkylation and evaluation of their anti-HIV activity

The total asymmetric synthesis of (+)- and (−)-clusianone and (+)- and (−)-clusianone methyl enol ether is reported. Asymmetric induction is achieved through the use of ACC alkylation, providing the key intermediates with an er of 99:1. The four synthetic compounds were evaluated for their anti-HIV activity. Both (+)- and (−)-clusianone displayed significant anti-HIV activity.     

Microbial transformations 59: first kilogram scale asymmetric microbial Baeyer-Villiger oxidation with optimized productivity using a resin-based in situ SFPR strategy

This study is demonstrating the scale up of asymmetric microbial Baeyer-Villiger oxidation of racemic bicyclo[3.2.0]hept-2-en-6-one (1) to the kilogram scale using a 50 L bioreactor. The process has been optimized with respect to bottlenecks identified in downscaled experiments. A high productivity was obtained combining a resin-based in situ substrate feeding and product removal methodology (in situ SFPR), a glycerol feed control, and an improved oxygenation device (using a sintered-metal sparger). As expected both regioisomeric lactones [(-)-(1S,5R)-2 and (-)-(1R,5S)-3] were obtained in nearly enantiopure form (ee > 98%) and good yield. This represents the first example of such an asymmetric Baeyer-Villiger biooxidation reaction ever operated at that scale. This novel resin-based in situ SFPR technology therefore clearly opens the way to further (industrial) upscaling of this highly valuable (asymmetric) reaction.     

Total synthesis and antifungal activity of (2S,3R)-2-aminododecan-3-ol

We report the total synthesis of (2S,3R)-2-aminododecan-3-ol has been achieved starting from commercially available 10-undecenoic acid. The key steps involved are Sharpless asymmetric epoxidation, Miyashita's boron-directed C-2 regioselective azidolysis, generated the asymmetric centers and in situ detosylation and reduction of azido tosylate. The antifungal activity of the synthesized (2S,3R)-2-aminododecan-3-ol was evaluated on several Candida strains and was comparable to miconazole, a standard drug.     

Bicyclic glutamic acid derivatives

For the second-generation asymmetric synthesis of the trans-tris(homoglutamic) acids via Strecker reaction of chiral ketimines, the cyanide addition as the key stereodifferentiating step produces mixtures of diastereomeric alpha-amino nitrile esters the composition of which is independent of the reaction temperature and the type of the solvent, respectively. The subsequent hydrolysis is exclusively achieved with concentrated H(2)SO(4) yielding diastereomeric mixtures of three secondary alpha-amino alpha-carbamoyl-gamma-esters and two diastereomeric cis-fused angular alpha-carbamoyl gamma-lactams as bicyclic glutamic acid derivatives, gained from in situ stereomer differentiating cyclisation of the secondary cis-alpha-amino alpha-carbamoyl-gamma-esters. Separation was achieved by CC. The pure secondary trans-alpha-amino alpha-carbamoyl-gamma-esters cyclise on heating and treatment with concentrated H(2)SO(4), respectively, to diastereomeric cis-fused angular secondary alpha-amino imides. Their hydrogenolysis led to the enantiomeric cis-fused angular primary alpha-amino imides. The configuration of all compounds was completely established by NMR methods, CD-spectra, and by X-ray analyses of the (alphaR,1R,5R)-1-carbamoyl-2-(1-phenylethyl)-2-azabicyclo[3.3.0]octan-3-one and of the trans-alphaS,1S,2R-2-ethoxycarbonylmethyl-1-(1-phenylethylamino)cyclopentanecarboxamide.     

First asymmetric synthesis of (-)-lintetralin via intramolecular Friedel-Crafts-type cyclization

The asymmetric synthesis of an aryltetralin lignan, (-)-lintetralin, was achieved with an overall yield of 29% with seven steps. Key features of the synthesis are an asymmetric Strecker reaction, a diastereoselective Michael addition of the lithiated amino nitrile product to 5H-furan-2-one, and an intramolecular carbocationic cyclization to provide the desired ring skeleton with the correct configuration.     

Biomimetic synthesis of acid-sensitive (-)- and (+)-caparrapi oxides, (-)- and (+)-8-epicaparrapi oxides, and (+)-dysifragin induced by artificial cyclases

Asymmetric total syntheses of acid-sensitive (-)- and (+)-caparrapi oxides (1) and (+)-8-epicaparrapi oxide (2) from farnesol (10) are achieved using Sharpless-Katsuki epoxidation and Lewis acid-assisted chiral Br?nsted acid (chiral LBA)-induced polyene cyclization as key steps. The relative configuration of (+)-dysifragin (4) is determined by a single-crystal X-ray diffraction and its total synthesis is accomplished by the diastereoselective epoxidation of (+)-1. Furthermore, (-)-1 can be directly synthesized from (S)-nerolidol (3) and (R)-LBA with 88% ds by reagent control, which overcame substrate control, while (-)-2 is obtained from (R)-3 and (R)-LBA with >99% ds by the double asymmetric induction.     

Practical, asymmetric synthesis of 16-hydroxyeicosa-5(Z),8(Z), 11(Z),14(Z)-tetraenoic acid (16-HETE), an endogenous inhibitor of neutrophil activity

An asymmetric synthesis of 16-HETE, an endogenous inhibitor of neutrophil activity, was achieved in six steps from R-(-)-glycidyl benzyl ether in 28% overall yield.     

Analysis of optical purity and impurity of synthetic D-phenylalanine products using sulfated beta-cyclodextrin as chiral selector by reversed-polarity capillary electrophoresis

A new capillary electrophoresis (CE) method has been achieved for simultaneous separation and quantification of phenylalanine, N-acetylphenylalanine enantiomers, and prochiral N-acetylaminocinnamic acid, possibly co-existent in reaction systems or synthesized products of D-phenylalanine. The separation was carried out in an uncoated capillary under reversed-electrophoretic mode. Among the diverse charged cyclodextrins (CDs) examined, highly sulfated (HS)-beta-CD as the chiral selector exhibited the best enantioselectivity. The complete separation of the analytes was obtained under the optimum conditions of pH 2.5, 35 mM Tris buffer containing 4% HS-beta-CD, applied voltage -15 kV, and capillary temperature 25 degrees C. Furthermore, the proposed method was applied to the determination of optical purity and trace impurities in three batches of the asymmetric synthetic samples of D-phenylalanine, and satisfactory results were obtained. The determination recoveries of the samples were in the range of 97.8-103.8%, and precisions fell within 2.3-5.0% (RSD). The results demonstrate that this CE method is a useful, simple technique and is applicable to purity assays of D-phenylalanine.     

Recent development of asymmetric syntheses based on the Meerwein-Ponndorf-Verley reduction

Stereoselective Meerwein-Ponndorf-Verley (MVP) reductions, including intermolecular MPV reductions, intramolecular MPV reductions (asymmetric 1,5- and 1,7-hydride shifts), catalytic MPV reduction, and reactions related to the MPV reduction are reviewed from the standpoint of asymmetric synthesis.     

Toluene bioconversion to p-hydroxybenzoate by fed-batch cultures of recombinant Pseudomonas putida.

A microbial oxidation process for the production of p-hydroxybenzoate (HBA) from toluene is reported. The oxidation reaction was studied in fed-batch fermentations using a recombinant Pseudomonas putida grown on glutamate as the sole carbon and energy source with salicylate and IPTG induction of tmoABCDE, and pchCF and phbz pathway genes, respectively. An average volumetric HBA productivity of 13.4 mg HBA x L(-1) x h(-1) was obtained under rapid growth conditions (glutamate excess), giving an HBA titer of 132 mg x L(-1) after 9.8 h of fermentation. This corresponded to an average specific HBA productivity of 7.2 microg HBA (mg total protein)(-1) x h(-1). In contrast, maximum HBA titers of 35 mg HBA x L(-1) were achieved in 27 h in comparative studies employing glutumate limited fed-batch cultures. A specific productivity of 4.1 microg HBA (mg total protein)(-1) x h(-1) and volumetric productivity of 1.3 mg HBA x L(-1) x h(-1) were calculated for the growth-rate restricted cultures. The differences in HBA production between the two cultures could be correlated to the levels of specific toluene-4-monooxygenase (T4MO) polypeptides. T4MO catalyzes the rate-limiting step in the pathway. Using experimental data, the half-life value of TmoA was calculated to be approximately 28 h. Assuming linear, monomolecular decay of TmoA, a specific degradation constant of 0.025 x h(-1) was calculated, which placed the stability of recombinant TmoA in the range of relatively stable proteins, even in the absence of co-expression of tmoF, the terminal oxidoreductase subunit of T4MO.     

Highly enantioselective synthesis, crystal structure, and circular dichroism spectroscopy of (R)-bambuterol hydrochloride

The present article describes the asymmetric synthesis of (R)-bambuterol hydrochloride based on 1-(3,5-dihydroxyphenyl)ethanone as starting material, which was esterified by dimethylcarbamic chloride, and brominated by copper (II) bromide. Then the carbonyl group was reduced efficiently using (-)-B-chlorodiisopinocamphenylborane [(-)-DIP-chloridetrade mark] as an asymmetrical reducing agent. Followed by epoxide ring closure with NaOH and ring expansion with tert-butylamine led to the desired product (R)-bambuterol with e.e. up to 99%. The optical properties and absolute configuration of (R)-bambuterol hydrochloride were further investigated using circular dichroism spectroscopy and X-ray single crystal analysis.     

Asymmetric synthesis of (R)-2-chloro-1-(m-chlorophenyl)ethanol using acetone powder of Geotrichum candidum

The asymmetric synthesis of (R)-2-chloro-1-(m-chlorophenyl)ethanol, a precursor for a key intermediate of an important class of drugs, was achieved by reduction of the corresponding ketone using an acetone powder of Geotrichum candidum with 98% ee and 94% yield based on the starting amount of ketone.     

Axially dissymmetric N-thioacylated (S)-(-)-1,1'-binaphthyl-2,2'-diamine ligands for copper-catalyzed asymmetric Michael addition of diethylzinc to alpha,beta-unsaturated ketone

Axially chiral thioamide ligands L5, L6, L8, L11, and bis(thioamide) ligand L13 were prepared from the reaction of (S)-(-)-1,1'-binaphthyl-2,2'-diamine with acyl chlorides and phosphorus pentasulfide (P2S5). The catalytic asymmetric 1,4-addition of diethylzinc to alpha,beta-unsaturated ketones was examined using this novel chiral ligand system with 28-73% ee in moderate to good yields.     

Enantioselective synthesis of (R)‐Cinacalcet via cobalt‐catalysed asymmetric Negishi cross‐coupling

A novel enantioselective synthesis of (R)‐cinacalcet with 99% enantiomeric excesses (ee) has been achieved. The main strategies of the approach include a gram‐scale cobalt‐catalysed asymmetric cross‐coupling of racemic ester with arylzinc reagent, Hoffman‐type rearrangement of acidamide, the amidation of chiral amine, and improving the ee of chiral amide from 87% to 99% via recrystallization.     

Chiral synthesis via organoboranes. 41. The utility of B-chlorodiisopinocampheylborane for a general synthesis of enantiomerically pure drugs

A general approach to the synthesis of enantiomerically pure α-phenyl amino alcohols via the asymmetric reduction of α-phenyl haloalkyl ketones or α-phenyl aminoalkyl ketones with B-chlorodiisopinocampheylborane is described. Using this approach, an improved synthesis of a potential antipsychotic, α-(4-fluorophenyl)-4-(2-pyrimidinyl)-1-piperazinebutanol in ⩾98% ee, and the broncholdilator 1-(2-methoxy-2-phenethyl)-4-(3-hydroxy-3-phenylpropyl)piperazine (eprozinol) in ⩾99% ee is achieved. © 1995 Wiley-Liss, Inc.     

Chiral cinchona alkaloid-derived thiourea catalyst for enantioselective synthesis of novel β-amino esters by Mannich reaction

A cinchona alkaloid-derived thiourea catalyst has been designed to access new asymmetric β-amino esters bearing benzothiazole moiety by utilizing a Mannich reaction between an imine and a malonate. A simultaneous activation of the two imine functionalities and malonate by the bifunctional chiral organocatalyst is proposed to account for the good yields (71-91%) and high enantiomeric excess (89.4-98.5%) under mild conditions.     

G‐quadruplex DNA‐based asymmetric catalysis of michael addition: Effects of sonication,ligands, and co‐solvents

There is an escalating interest of using double stranded DNA molecules as a chiral scaffold to construct metal‐biomacromolecule hybrid catalysts for asymmetric synthesis. Several recent studies also evaluated the use of G‐quadruplex DNA‐based catalysts for asymmetric Diels‐Alder and Friedel‐Crafts reactions. However, there is still a lack of understanding of how different oligonucleotides, salts (such as NaCl and KCl), metal ligands and co‐solvents affect the catalytic performance of quadruplex DNA‐based hybrid catalysts. In this study, we aim to systematically evaluate these key factors in asymmetric Michael addition reactions, and to examine the conformational and molecular changes of DNA by circular dichroism (CD) spectroscopy and gel electrophoresis. We achieved up to 95% yield and 50% enantiomeric excess (ee) when the reaction of 2‐acylimidazole 1a and dimethylmalonate was catalyzed by 5′‐G₃(TTAG₃)₃?3′ (G4DNA1) in 20 mM MOPS (pH 6.5) containing 50 mM KCl and 40 µM [Cu(dmbipy)(NO₃)₂], and G4DNA1 was pre‐sonicated in ice bath for 10 min prior to the reaction. G‐quadruplex‐based hybrid catalysts provide a new tool for asymmetric catalysis, but future mechanistic studies should be sought to further improve the catalytic efficiency. The current work presents a systematic study of asymmetric Michael addition catalyzed by G‐quadruplex catalysts constructed via non‐covalent complexing, and an intriguing finding of the effect of pre‐sonication on catalytic efficiency. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:891–898, 2016     

Asymmetric transformation of a racemic α-(phthalimidooxy)arylacetic ester by a combination of preferential crystallization and simultaneous racemization

An asymmetric transformation of racemic t-butyl 2-(3,4-O-carbonyldioxy-phenyl)-2-(phthalimidooxy)acetate [(RS)- 2b ] into one of its optically active forms was carried out by a combination of preferential crystallization of a desired enantiomer and the simultaneous racemization of the antipode. (R)- 2b was easily racemized in diethylketone in the presence of a small amount of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Under the conditions for racemization, the asymmetric transformation was achieved successfully to give (S)- 2b with 84% optical purity in 80% yield. A potent antipseudomonal cephalosporin M-14659 ( 1 ) was prepared from the pure (S)- 2b which was obtained by the recrystallization of the crude (S)- 2b . © 1993 Wiley-Liss, Inc.