Asymmetric induction in catalyzed synthesis of organic compounds as an important stage in the evolution of life on earth

It is shown that natural chiral catalysts, which could be formed e.g., from optically active amino acids on basic natural minerals, could lead, at early stages of evolution, to the formation of rather complex optically active products from starting achiral compounds. Using biomimetic combinations of vanadium ion complexes and chiral ligands synthesized from widely occurring natural compounds, we created novel catalytic systems, permitting the transfer of optical activity in the course of catalytic chemical transformations of achiral compounds. We found that in the presence of natural clay, optically active terpenoids from the pinane series undergo multistage transformations, forming unexpected new products with preservation of optical purity.     

Spontaneous Generation of Chirality in Simple Diaryl Ethers

We studied the spontaneous formation of chiral crystals of four diaryl ethers, 3‐phenoxybenzaldehyde, 1 ; 1,3‐dimethyl‐2‐phenoxybenzene, 2 ; di(4‐aminophenyl) ether, 3 ; and di(p‐tolyl) ether, 4 . Compounds 1 , 3 , and 4 form conformationally chiral molecules in the solid state, while the chirality of 2 arises from the formation of supramolecular helices. Compound 1 is a liquid at ambient temperature, but 2 , 3 , 4 are crystalline, and solid‐state CD‐spectroscopy showed that they could be obtained as optically active bulk samples. It should be noted that the optical activity arise upon crystallization, and no optically active precursors were used. Indeed, even commercial samples of 3 and 4 were found to be optically active, giving evidence for the ease at which total spontaneous resolution may occur in certain systems. Chirality 27:425‐429, 2015. © 2015 Wiley Periodicals, Inc.     

Racemization in the synthesis of sequential polypeptides using N-hydroxysuccinimide esters

Racemization in the synthesis of peptide intermediates and their polymers was investigated, using L-amino acid oxidase. The formation of N-hydroxysuccinimide esters from N-protected peptide acids yielded optically pure products in contrast to p-nitrophenyl and pentachlorophenyl active esters. The racemization in the polymerization step was found to be base sensitive. Partially racemized polymer can result from optically homogeneous monomer. Thus, the optical integrity of active monomer species carries no guarantee for that of the polymer.     

A model of dirigent proteins derived from structural and functional similarities with allene oxide cyclase and lipocalins

Dirigent proteins impart stereoselectivity on the phenoxy radical-coupling reaction, yielding optically active lignans from two molecules of coniferyl alcohol. By an unknown mechanism, they direct the coupling of two phenoxy radicals toward the formation of optically active (+)- or (-)-pinoresinol. We show here that the dirigent protein AtDIR6 from Arabidopsis thaliana is a homodimeric all-beta protein in the superfamily of calycins. Based on its homology with calycins, the structure of AtDIR6 was modeled using allene oxide cyclase as template. The structural model of AtDIR6 was supported experimentally by confirmation of a predicted disulfide bridge and by the characterization of two N-linked glycans at the solvent-exposed protein surface. The model shows AtDIR6 as an eight-stranded antiparallel β-barrel with a central hydrophobic cavity for substrate binding, suggesting that dirigent proteins evolved from hydrophobic ligand-binding proteins. The data are fully consistent with the current view of the dirigent protein mode of action, according to which each subunit of the homodimer captures one of the substrate radicals and orients them in a way that precludes undesired reaction channels, thus favoring the formation of the optically pure coupling product.     

Cytokinin-induced shoot formation

Zeatin, (±)-dihydrozeatin and optically active cytokinins (asymmetric carbon α to the exocyclic nitrogen) were tested for their ability to induce development of shoots in tobacco callus. Zeatin and dihydrozeatin were equally active. The levorotatory compounds tested were active in inducing shoot formation but the corresponding dextrorotatory compounds were inactive at all concentrations tested. These findings suggest that the group attached to the N⁶ position of cytokinins binds to a receptor site to bring about organ formation.     

Optical activity and evolution

It is noted that the chemical reactions occurring in rarefied cosmic clouds (molecular concentration 10² cm^–3) differ from similar laboratory reactions by the much greater effect on the outcome of external force fields. In this light it is hypothesized that the synthesis of optically active substances may occur in the outer space under the conjoint stereospecific effect of a magnetic and other molecule-orienting field. It is further conjectured that the optically active substances of the Solar System had been produced in the course of its formation out of the primal rarefied cloud.     

Catalytic diastereoselective sulfimidation of diaryl sulfides and application of chiral sulfimides to asymmetric allylic alkylation

The copper-catalyzed diastereoselective imidation of diaryl sulfides bearing a chiral oxazolinyl moiety at the ortho-position with [N-(p-toluenesulfonyl) imino]phenyliodinane (TsN=IPh) or Chloramine-T trihydrate [TsN(Cl)Na.3H2O] was successfully carried out to give the corresponding optically active N-tosylsulfimides in good yields. For example, the imidation of diphenyl sulfide bearing a methoxymethyl moiety at the 4-position of the oxazoline ring with TsN(Cl)Na.3H2O in acetonitrile in the presence of 10 mol% Cu(OTf)2 at 25 degrees C for 24 h affords the corresponding optically active N-tosylsulfimide in 52% isolated yield with a high diastereoselectivity of 99%. Hydrolysis of the optically active N-p-tosylsulfimides converts them into the corresponding optically active sulfimides in high yields without loss of diastereoselectivity. These novel optically active sulfimides and N-tosylsulfimides work as efficient chiral ligands for palladium(II)-catalyzed allylic alkylation of 1, 3-diphenyl-3-acetoxy-1-propene with dimethyl malonate to give the corresponding alkylation product quantitatively and with a high stereoselectivity (up to 90% ee).     

Role of racemization in optically active drugs development

U.S. Food and Drug Administration issues certain guidelines for marketing of optically active drugs as some enantiomers racemize into human body, leading to the generation of other antipodes, which may be toxic or ballast to the human beings. Moreover, racemization reduces the administrated dosage concentration as optically active enantiomer converted into its inactive counter part. Therefore, the study of racemization of such type of drugs is an important and urgent need of today. This article describes in vitro and in vivo racemization of optically active drugs. The racemization process of various optically active drugs has been discussed considering the effect of different variables i.e. pH, temperature, concentration of the drug, ionic concentration, etc. Attempts have also been made to discuss the mechanisms of racemization. Besides, efforts have been made to suggest the safe dosages of such type of drugs too.     

Synthesis of racemic and optically active glycidic ethers,precursors of liquid crystalline polyethers

A series of racemic and optically active oxiranes, bearing mesogenic groups, precursors of liquid crystalline polyethers, has been synthesized from epichlorohydrin or glycidol. The enantiomeric excess of the optically active oxiranes has been determined by chiral stationary phase HPLC. Compounds bearing 4-cyanobiphenyl mesogenic group exhibit monotropic liquid crystalline behavior. A transfer of chirality to the mesophase has been observed for the optically active oxiranes, which present a cholesteric phase. Chirality 10:779–785, 1998. © 1998 Wiley-Liss, Inc.     

Preparation and isolation of 2-methylamino-3-phenylpropanoic acid enantiomers using selective crystallization

First, (RS)-2-chloro-3-phenylpropanoic acid [(RS)-CPP] was optically resolved using ethyl (S)-phenylalaninate as a resolving agent, aiming at preparation of optically active 2-methylamino-3-phenylpropanoic acid (MPP). The (R)-CPP obtained as the sodium salt monohydrate was reacted with methylamine to give (S)-2-methylamino-3-phenylpropanoic acid [(S)-MPP]. Next, the optical resolution of (RS)-MPP was also attempted via molecular compound formation with optically active mandelic acid (MAN). The molecular compound of (R)-MPP with (S)-MAN [(R)-MPP (S)-MAN] was obtained as the less soluble diastereomeric compound, while the (S)-MPP (S)-MAN compound was found to be the more soluble one. Recrystallization of (R)-MPP (S)-MAN compound from water, followed by treatment with acetone, gave optically pure (R)-MPP in 79% yield, based on a half amount of the starting (RS)-MPP. The (S)-MPP obtained from (S)-MPP (S)-MAN compound was again subjected to formation of molecular compound with (R)-MAN to give optically pure (S,)-MPP in 66% yield. Chirality 9:386–389, 1997. © 1997 Wiley-Liss, Inc.     

Structural characteristics of dry blood serum of patients with arteriosclerosis after plasmapheresis

The surface of dried drops of blood serum (BS) from 86 plasmapheresis patients with atherosclerosis has been studied for its structural peculiarities. The content of lipids (total cholesterol, cholesterol of lipoproteins of high density, triglycerides), sialic acids and immunoglobulins was determined in all the examinees. BS from 20 practically healthy people was taken as a control. Optically inactive filamentous dichotomically branching crystals were typical of its microstructure. Optically active spherolites were found in patients with high content of cholesterol, optically active dendrite aggregation--in patients with high content of triglycerides, optically active fibrils appeared in case of hypersialemia, optically inactive aggregates--in case of hyperimmunoglobulemia. The plasmapheresis course carried out in patients was followed by appearance of filamentous dichotomically branching crystals, and disappearance of optically active inclusions, that testified to ordering of the BS structure. The results obtained were confirmed by normalization of the content of lipids, sialic acids, immunoglobulins.     

Interaction of antimalarial drugs with hemin

Hemin (ferriprotoporphyrin IX) is shown to form complexes with the chloroquine class of antimalarial drugs. The Soret band of hemin becomes optically active upon the addition of chiral drugs. Results on the hemin-induced quenching of the fluorescence of chloroquine are consistent with the formation of a 2:1 hemin:drug complex with a formation constant of 1.4 x 10(7) at 298 K. Also a direct comparison of the drug-treated and drug-free parasites themselves, by the noninvasive photoacoustic spectroscopic method, reveals an in vivo interaction between endogenous hemin and the added drug.     

Enantioselective photoreaction of achiral tropolone ether in inclusion crystals with optically active host compounds

Achiral 4-isopropyltropolone methyl ether (3) included in an optically active host compound (-)-1 yielded optically active photocyclization products (-)-5 and (-)-6 in 96 and 90% ee, respectively, upon photoirradiation in the solid state.     

Novel synthesis of optically active bishomotyrosine derivatives using the Friedel-Crafts reaction in triflic acid

We report here a novel synthesis of optically active bishomotyrosine. The bishomotyrosine skeleton was constructed by using a Friedel-Crafts reaction between phenol and optically active N-Tfa-Glu(Cl)-OMe in triflic acid under the mild condition. Reduction and subsequent deprotection then afforded bishomotyrosine derivatives without any loss of optical purity.     

Different behavior toward racemization in basic media from chiral analogs of clofibric acid, the active metabolite of the antilipidemic drug clofibrate

Some chiral analogs of clofibric acid, the active metabolite of the antilipidemic drug clofibrate, show different configurational stability in basic conditions. Also, extensive racemization occurs when the corresponding optically active acid chlorides are treated with 3 alpha-tropanol, whereas no racemization takes place with 3 alpha-tropanol as hydrochloride salt and with 3 beta-tropanol and 1-methyl-4-hydroxy-piperidine as either the free base or hydrochloride salt. For these aminoalcohols, experimental evidence supports the hypothesis that a ketene intermediate is involved in the racemization process. Formation of intramolecular hydrogen bond is evoked to explain the different ability of aminoalcohols to induce ketene formation and consequent racemization.     

Novel Synthesis of Optically Active Bishomotyrosine Derivatives Using the Friedel-Crafts Reaction in Triflic Acid

We report here a novel synthesis of optically active bishomotyrosine. The bishomotyrosine skeleton was constructed by using a Friedel-Crafts reaction between phenol and optically active N-Tfa-Glu(Cl)-OMe in triflic acid under the mild condition. Reduction and subsequent deprotection then afforded bishomotyrosine derivatives without any loss of optical purity.     

Biomimetic asymmetric oxidative coupling of phenols

This paper describes the first examples of asymmetric induction in the oxidative coupling of phenols using chiral oxidants. When chiral cupric-amine complexes were used as oxidants, low asymmetric induction was achieved in the coupling of naphthols. The formation of optically active d-dehydrogriseofulvin and l-Licarin A using the cupric-l-a-phenylethylamine complex perhaps mimics the action of copper-containing enzymes known to catalyze phenol coupling.     

Synthesis of a novel ester analog of nucleic acids bearing a serine backbone

A novel analog of nucleic acids bearing an optically active serine ester backbone, serine-based nucleobase-linked polyester (SNE), was synthesized. Monomers containing a thymine base were synthesized from L- and D-serines. Furthermore, reaction conditions were thoroughly examined for the ester bond formation by using a new phosphonium-type condensing reagent on a solid support without racemization. The release of the dimer from the resin was also investigated using a new type of linker, which could be cleaved under neutral conditions.     

Optical resolution by crystalline inclusion formation using new lactic acid derived hosts

New optically active host compounds for chiroselective crystalline inclusion formation derived from natural lactic acid are synthesized. They enable useful enantiomer separations of different chiral compounds via cocrystallization and sorption on preparative scale including various ketones, lactones, alcohols, sulfoxides, and methyloxiranes. In the cases of 3-methylcyclohexanone, 4-methyl-δ-valerolactone, and 2-phenylpropanol, ees > 99% were obtained from one cocrystallization step using these hosts. © 1993 Wiley-Liss, Inc.     

Synthesis of the optically active 4-O-phosphono-D-glucosamine derivatives related to the nonreducing-sugar subunit of bacterial lipid A

The optically active lipid A-subunit homologs named GLA-46, GLA-47, GLA-59, and GLA-60 have been synthesized stepwise by successive acylation at N-2 and O-3 of benzyl 2-amino-2-deoxy-4,6-O-isopropylidene-beta-D-glucopyranoside with the 3-9O-(benzyloxy)methyl or 39O-tetradecanoyl derivative of optically active 3-hydroxytetradecanoic acid, and phosphorylation at O-4 of the D-glucosamine residue.