Lipase-catalyzed kinetic resolution approach toward enantiomerically enriched 1-(β-hydroxypropyl)indoles

In a route towards enantiomerically enriched 1-(β-hydroxypropyl)indoles, which are potentially useful building blocks for high value-added chemicals synthesis, a kinetic resolution approach by means of lipase-catalyzed enantioselective acylation as well as hydrolysis/methanolysis has been elaborated for the first time. The enzymatic resolution of chiral N-substituted indole-based sec-alcohols was successfully accomplished, yielding both enantiomeric forms of the employed derivatives with up to >99% enantiomeric purity via an enantioselective transesterification under mild reaction conditions. The most selective resolutions were obtained using fungal (CAL-B and TLL) and bacterial (PFL and BCL) lipases and vinyl acetate as the acyl?group donor. The synthetic protocol described herein is very simple, user-friendly and efficient, thus paving the way for future access towards more complex compounds of this type. The absolute configurations of novel enantiomeric derivatives, and thus stereoselectivity of the described enzymatic reactions were confirmed by application of CDA-based NMR methodology and single-crystal X-ray diffraction analysis.     

Current applications of organocatalysts in asymmetric aldol reactions: An update

The aldol reaction is one of the most important carbon–carbon bond formations in synthetic organic chemistry. An enantioselective aldol reaction should provide an enantioenriched product. The organocatalytic asymmetric aldol reaction via an in situ generated enamine intermediate is one of the most powerful synthetic tools to achieve enantiomerically pure products. This approach is often used to obtain chiral β-hydroxycarbonyl compounds with excellent enantioselectivity. In this report, we update our previous review regarding the applications of organocatalysts in asymmetric aldol reactions leading to chiral β-hydroxycarbonyl compounds as versatile synthetic motifs frequently found in pharmaceutically desired intermediates and biologically active naturally occurring compounds.     

Synthesis of the four enantiomers of diethyl 1,2-di(N-Boc-amino)propylphosphonates

A simple and efficient synthetic strategy to all four enantiomerically pure diethyl 1,2-di(N-Boc-amino)propylphosphonates has been elaborated starting from the corresponding N-[(R)-(1-phenylethyl)]aziridine-(2S)- and N-[(S)-(1-phenylethyl)]aziridine-(2R)-carboxaldehydes, employing a one-pot three-components Kabachnik-Fields reaction followed by the hydrogenolytic removal of the chiral auxiliary and aziridine ring opening with simultaneous protection of the amino groups as the N-Boc derivatives.     

Review on asymmetric synthetic methodologies for chiral isoquinuclidines; 2008 to date

Isoquinuclidines constitute the central structural nucleus of numerous biologically active natural products, for example, iboga alkaloids such as ibogamine and catharanthine as well as non-indole-containing alkaloids such as the dioscorine and the cannivonines. Furthermore, in medicinal and pharmaceutical chemistry, the isoquinuclidine core is commonly employed as a rigid azabicyclic scaffold, thus providing significant precursors in the synthesis of numerous valuable alkaloids. Summarizing well-organized approaches to access the chiral isoquinuclidine structural centerpiece signifies a significant endeavor not only for developing biologically active natural products but also enhancing biological researches that can lead to possible drug discovery. Over time, the values and methodologies for the asymmetric synthesis of chiral isoquinuclidines are increasing; hence to advance asymmetric synthesis, this review combines and discusses the pros and cons of each synthesis techniques from 2008. This review should be helpful for promoting further developments of asymmetric synthetic methodologies and for medicinal chemistry.     

Asymmetric synthesis of 1,4-disubstituted 3-methylidenedihydroquinolin-2(1H)-ones

A series of enantiomerically pure or highly enriched (R)- or (S)-3-methylidenetetrahydroquinolin-2-ones was readily prepared by highly diastereoselective Michael additions of various Grignard reagents to quinolin-2(1H)-ones, containing an (R,R)- or (S,S)-di(1-phenylethylamino)phosphoryl group as chiral auxiliary, followed by Horner-Wadsworth-Emmons olefination of formaldehyde. An efficient synthesis of the starting (R,R)- and (S,S)-3-({di[(1-phenylethyl)amino]}phosphoryl)-1-alkyl-quinolin-2(1H)-ones is also described. The relative and absolute configurations of the intermediate adducts and final methylidenequinolinones were established by NMR and X-ray analysis.     

New N,N-diamine ligands derived from (−)-menthol and their application in the asymmetric transfer hydrogenation

Natural (?)-menthol was applied to construction of mono-N-tosylated-1,2-diamine derivatives. The O-tosylation and elimination of the tosylate of the menthol intermediate led to trans-p-menth-2-ene. The unsaturated menth-2-ene was next transformed into a mixture of N-tosylaziridines, which upon reaction with sodium azide gave four isomeric azides. The reduction of the formed tosylazides on Pd/C gave new chiral mono-N-tosylated-1,2-diamines, which were used as ligands in the asymmetric transfer hydrogenation protocol on aromatic ketones and endocyclic imine.     

Chiral benzimidazoles and their applications in stereodiscrimination processes

Chiral aspects of benzimidazoles have been over-shadowed for a long time due to the large number of reports on benzimidazoles in the medical field in numerous categories of therapeutic agents. The vigorous research activity in chiral applications of benzimidazole derivatives started after bifunctional benzimidazoles made their appearance especially in the last 2–3 decades. Thus, chiral benzimidazoles form a comparatively young branch of chiral chemistry. The presence of pyridine and pyrrole type of nitrogens along with the fused benzene ring confer on this class of molecules, special properties including useful nucleophilicity, hydrogen bonding ability and a rigid backbone, all of which play decisive roles in proven chiral applications. The present review aims to cover the synthetic routes to access chiral benzimidazoles and their applications in a plethora of chiral fields including enantioselective organocatalysis, metal-based catalysis, asymmetric transformations involving benzimidazole-N-heterocyclic carbenes, kinetic resolution, benzimidazole-based macrocyclic hosts in chiral supramolecular chemistry and other miscellaneous chiral applications.     

Asymmetric biosynthesis of intermediates of anti-HIV drugs

Human immunodeficiency virus (HIV) infection is the fifth most common cause of death and many new HIV infections occur every year. The prevalence of HIV also seriously affects the quality of a patient’s life. More than forty anti-HIV drugs have been put into clinical uses, many of which are chiral molecules with multiple stereogenic centers, for example abacavir, lamivudine, zidovudine, stavudine, tenofovir, atazanavir. However, the chemical synthesis of these chiral intermediates have the disadvantages of low enantiomeric purity and complex synthetic steps. The benefits of asymmetric biosynthesis of chiral drugs include high enantiomeric excess (e.e.), good product selectivity, mild reaction conditions, and less side effects. The biosynthesis of the chiral intermediates of these anti-HIV drugs is thus particularly important. Herein, we review the different sources of enzymes and microbial cells for the asymmetric biosynthesis of the above chiral anti-HIV drug intermediates. We also review recent biotechnology progress in engineering these enzymes and microbial cells with improved biocatalytic activities, including enzyme and cell immobilization, surface display of enzymes, and directed evolution of enzymes. These biotechnology processes enable the efficient biosynthesis of these chiral intermediates, facilitating the industrial production of anti-HIV drugs with reduced costs.     

A diversity oriented synthesis of d-erythro-sphingosine and siblings

An efficient building block-based synthetic protocol has been developed for the synthesis of 3-ketosphingoids with various chain lengths using cross metathesis of a Garner’s aldehyde-derived α,β-unsaturated ketone as the key step. Stereoselective reduction of the biomimetic precursors thus obtained provided d-erythro-sphingosine and truncated anaogues in good overall yields.     

O-(α-Phenylethyl)hydroxylamine as a ‘chiral ammonia equivalent’: synthesis and resolution of 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids

An approach to the synthesis and resolution of five- and six-membered lactams (i.e., 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids) is described. The method relies on the one-pot Michael reaction—cyclization of itaconic acid or diethyl homoitaconate and enantiopure O-(α-phenylethyl)hydroxylamine as a ‘chiral ammonia equivalent’. It is shown that this chiral auxiliary can be used for the separation of diastereomeric lactam products and then easily removed by catalytic hydrogenolysis.     

Hydroxy lactones with the gem-dimethylcyclohexane system – Synthesis and antimicrobial activity

Two new lactones comprising the gem-dimethylcyclohexane ring: 2-chloro-5,5-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one and 2-bromo-5,5-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one as well as the already known 2-iodo-5,5-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one, were obtained from (6,6-dimethylcyclohex-2-en-1-yl)acetic acid. These lactones were used as substrates for the screening of biotransformation by whole cells of nine fungal strains (Fusarium species, Syncephalastrum racemosum and Cunninghamella japonica). Some of these microorganisms (mainly Fusarium species) transformed all three lactones during the hydrolytic dehalogenation into 2-hydroxy-5,5-dimethyl-9-oxabicyclo[4.3.0]nonan-8-one. It is worth noting that two microorganisms (Fusarium culmorum and Fusarium scirpi) converted iodolactone with very high enantioselectivity (75.1% and 91.6%, respectively). The (+) isomer of hydroxy lactone was preferred. At the last step the hydroxy lactone obtained during biotransformation was examined for its biological activity against bacteria, yeasts and fungi. It was found that this compound inhibits growth of some tested microorganisms.     

Features of electronic circular dichroism and tips for its use in determining absolute configuration

This review focuses on the general features of electronic circular dichroism (ECD) as applied in determining the absolute configuration of organic compounds. The high sensitivity and straightforward spectral interpretation of the exciton chirality method makes this approach very useful, and complementary to X-ray crystallography. A brief tutorial is provided on ECD, with precautions and tips for using it, especially the exciton chirality method. The spectroscopic ECD of several examples are analyzed.     

A concise enantioselective synthesis of 1,4-dideoxy-1,4-imino-d-arabinitol using Co(III)(salen)-catalyzed hydrolytic kinetic resolution of a two-stereocentered anti-azido epoxide

A concise enantioselective synthesis of 1,4-dideoxy-1,4-imino-d-arabinitol, (+)-DAB-1, has been described in good overall yield (18.1%) and with high enantiomeric purity (up to 98% ee) starting from a simple raw material, cis-2-butene-1,4-diol. The Co-catalyzed hydrolytic kinetic resolution of a two-stereocentered racemic azido epoxide followed by asymmetric dihydroxylation of the alkene and ‘one pot’ reductive cyclisation of the azido diol are key reactions in the synthetic sequence.     

Solvent-induced chirality switching in the enantioseparation of regioisomeric hydroxyphenylpropionic acids via diastereomeric salt formation with (1R,2S)-2-amino-1,2-diphenylethanol

The enantioseparation of three hydroxyphenylpropionic acid isomers via diastereomeric salt formation with (1R,2S)-2-amino-1,2-diphenylethanol has been demonstrated. The racemates of all three acid isomers were successfully separated with high efficiency (0.56–0.84) after single crystallization. For 2-hydroxy-3-phenylpropionic acid 4, the configuration of the less-soluble salt was controlled by the crystallization solvent: the (R)-4 salt was crystallized from water, while 2-propanol afforded the (S)-4 salt. The chiral recognition mechanism of the three acids was discussed based on the crystal structures of the diastereomeric salts.     

Amino-phenol complexes of Fe(III) as promising T1 accelerators

Iron(III) complexes with N,O-ligands are compounds of high interest because they can be applied in catalysis and play an important role in living organisms, e.g., as models of catechol dioxygenase. Several N,O-ligands were studied: their synthesis, iron(III) complexation and the potential of the latter as T₁-MRI contrast agents. A route to the tetrapodal N₃O₂-naphthyl ligand was investigated. The resulting iron complex was obtained in 26% total yield and its relaxivity value was moderate (r₁ = 1.03 in water and 2.54 s^?1 mM^?1 in serum). Thus, phenyl isomeric salan complexes were obtained. These complexes differed in charge (positive and neutral) and in the presence of polar hydrogen-bonding substituents. The highest relaxivities (r₁ = 2.39 in water and 5.37 s^?1 mM^?1 in serum) were obtained for the Fe(III) cationic complex with MeO groups in the ligand. EPR studies confirmed a high spin configuration of rhombically distorted Fe(III) complexes.     

[3+2]‐Cycloaddition for Fully Decorated Vinyl‐1,2,3‐Triazoles: Design,Synthesis and Applications

The s mall heterocyclic ring of the 1,2,3‐triazole module is one of the most widely investigated compounds in numerous applications of biological, medicinal, pharmaceutical and materially important molecules. In this regard, a large number of synthetic methodologies and approaches have already been reported to construct such a heterocyclic core structure in a selective manner. However, the vinyl‐substituted 1,2,3‐triazole moiety is another privileged segment in heterocyclic chemistry. The selective introduction of simple vinyl and functionalized vinyl groups onto the three different positions of the 1,2,3‐triazole framework can significantly improve the properties of the molecule. Accordingly, high‐yielding efficient approaches for the selective construction of vinyl‐containing 1,2,3‐triazoles becomes a promising branch of chemistry among practitioners of industry and academia. In this minireview, we have discussed recent advances in the construction of highly selective three different vinyl‐containing 1,2,3‐triazoles. In addition, representative synthetic methodologies and approaches for the corresponding three different classes of vinyl‐1,2,3‐triazoles and their applications have been described as well in this review.     

Application of titanium catalysts for the syntheses of heterocycles

The metal catalyzed synthesis of heterocycles is becoming an important and highly rewarding protocol in organic synthesis. Traditional approaches require expensive or highly specialized equipment or would be of limited use to the synthetic organic chemist due to their highly inconvenient approaches. Titanium-mediated cyclization reactions have been recognized as some of the simplest and useful tools for regio- as well as stereoselective syntheses of five-membered N-heterocycles. This review summarizes the applications of titanium catalysts with emphasis of their synthetic applications for different heterocylces. This review covered interesting discoveries in the past few years.     

Synthesis,crystal structure,and absolute configuration of the enantiomers of chiral drug xibenolol hydrochloride

Based on the features of its crystallization, racemic 3-(2,3-dimethylphenoxy)propane-1,2-diol 2, the synthetic precursor of the chiral drug xibenolol 1, was resolved into pure enantiomers by the direct method of entrainment. The enantiomers of diol 2 through a Mitsunobu reaction were converted into the nonracemic 1,2-epoxy-3-(2,3-dimethylphenoxy)propanes (S)- and (R)-3, and then into the xibenolol enantiomers. Single crystals of (+)- and (?)-1·HCl were studied by X-ray diffraction. On the basis of the Flack parameter, the absolute (R)- and (S)-configurations were assigned to these compounds and to the other intermediate chiral substances.     

Design and synthesis of ansamycin antibiotics

Ansamycin antibiotics are a class of microbial metabolites that exhibit an array of biological activities. This review covers the synthetic chemistry and biological activity of benzenic ansamycins from 1989 to 2007. In the first section, synthetic approaches to the C15-benzene ansamycins (geldanamycin and related) are discussed. Access to the C17-benzene ansamycins (or ansatrienins) is disclosed in the second half of this article.