Amino Alcohols as Potential Antibiotic and Antifungal Leads

Five focused compound libraries (forty-nine compounds), based on prior studies in our laboratory were synthesized and screened for antibiotic and anti-fungal activity against S. aureus, E. coli, K. pneumoniae, P. aeruginosa, A. baumannii, C. albicans and C. neoformans. Low levels of activity, at the initial screening concentration of 32 μg/mL, were noted with analogues of (Z)-2-(3,4-dichlorophenyl)-3-phenylacrylonitriles which made up the first two focused libraries produced. The most promising analogues possessing additional substituents on the terminal aromatic ring of the synthesised acrylonitriles. Modifications of the terminal aromatic moiety were explored through epoxide installation flowed by flow chemistry mediated ring opening aminolysis with discreet sets of amines to the corresponding amino alcohols. Three new focused libraries were developed from substituted anilines, cyclic amines, and phenyl linked heterocyclic amines. The aniline-based compounds were inactive against the bacterial and fungal lines screened. The introduction of a cyclic, such as piperidine, piperazine, or morpholine, showed >50% inhibition when evaluated at 32 μg/mL compound concentration against methicillin-resistant Staphylococcus aureus. Examination of the terminal aromatic substituent via oxirane aminolysis allowed for the synthesis of three new focused libraries of afforded amino alcohols. Aromatic substituted piperidine or piperazine switched library activity from antibacterial to anti-fungal activity with ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-methylpiperazin-1-yl)propoxy)phenyl)acrylonitrile), ((Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(4-(4-hydroxyphenyl)piperazin-1-yl)propoxy)-phenyl)acrylonitrile) and ((Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile) showing >95% inhibition of Cryptococcus neoformans var. grubii H99 growth at 32 μg/mL. While (Z)-3-(4-(3-(cyclohexylamino)-2-hydroxypropoxy)phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile, (S,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (R,Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)acrylonitrile, (Z)-2-(3,4-dichlorophenyl)-3-(4-(2-hydroxy-3-(D-11-piperidin-1-yl)propoxy)phenyl)-acrylonitrile, and (Z)-3-(4-(3-(4-cyclohexylpiperazin-1-yl)-2-hydroxypropoxy)-phenyl)-2-(3,4-dichlorophenyl)-acrylonitrile 32 μg/mL against Staphylococcus aureus.     

Dienic sex pheromones : Stereoselective syntheses of (7E,9Z)-7,9-dodecadien-1-yl acetate, (E)-9,11-dodecadien-1-yl acetate,and of (9Z), 11E)-9,11- tetradecadien-1-yl acetate by palladium-catalyzed reactions

Pure (7E,9Z-7, 9-dodecadien-1-yl acetate (1), the sex pheromone of Lobesiabotrana, has been prepared in 21.6% overall yield by a reaction scheme involving; (i) the cross-coupling of (E) - 8 - (2 - tetrahydropyranyloxy) -1 - octenyldisiamylborane with 1 - bromo - 1 - butyne, in the presence of a Pd (O) catalyst and base; (ii) the acetylation of the crude product of this reaction; (iii) the (Z)-stereoselective reduction of the obtained conjugated (E)-enyn-1-yl acetate. (E)-9,11-Dodecadien-1-yl acetate (2), a sex pheromone component of Diparopsiscastanea, has been analogously obtained (in 54.3% overall yield) by cross-coupling of (E) - 10 - (2 - tetrahydropyranyloxy) - 1 - decenyl borane with vinyl bromide, in the presence of a Pd (O) catalyst and base, followed by acetylation of the crude product. Compound 2, which was 87.7% chemically pure, was purified by column chromatography over SiO₂-AgNO₃. Chemically pure (9Z, 11E) - 9,11 - tetradecadien - 1 - yl acetate (3), a sex pheromone component of Spodopteralittoralis, has been prepared (in 30.2% overall yield) by reaction of 10 - (2 - tetrahydropyranyloxy) - 1 - decynylamagnesium bromide with (E)-1-iodo-1-butene, in the presence of a Pd (O) catalyst, followed by acetylation of the crude product and by (Z)-stereoselective reduction of the obtained (E)-enyn-1-yl acetate.The stereoisomeric purity of 1, 2 and 3 has been evaluated by glc analysis on glass capillary columns or by reverse phase hplc analysis.     

Stereoselective carbon–carbon bond forming reactions of chiral cyclopent-2-enone and cyclopentene-1-methanol,both spiro-connecting a 1,2:5,6-di-O-isopropylidene-α-d-glucofuranosyl ring

The conjugate additions of a variety of organocopper reagents or dimethyl malonate anion to a spirocyclic cyclopent-2-enone connecting a 1,2:5,6-di-O-isopropylidene-α-d-glucofuranosyl ring as a constituent of the spiro structure, namely (1S,3R,4R,5R)-3,4-(isopropylidenedioxy)-1-[(1R)-1,2-(isopropylidenedioxy)ethyl]-2-oxa-spiro[4.4]non-6-en-8-one, proceeded stereoselectively in some cases affording a variety of β-functionalized cyclopentanone derivatives. The thermal treatment of (1S,3R,4R,5R)-7-(hydroxymethyl)-3,4-(isopropylidenedioxy)-1-[(1R)-1,2-(isopropylidenedioxy)ethyl]-2-oxaspiro[4.4]non-6-ene, another d-glucose-derived spirocyclic substrate, with triethyl orthoacetate in the presence of a catalytic amount of acid afforded the Claisen rearrangement product with a high level of diastereoselectivity.     

Cesium fluoride and tetra-n-butylammonium fluoride mediated 1,4-N-->O shift of disubstituted phenyl ring of a bicalutamide derivative

A novel 1,4-N→O migration of a disubstituted phenyl ring was observed during N-methylation of a bicalutamide derivative, (2S)-2-(tert-butyldimethylsilanyloxy)-N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenoxy)-2-methylpropionamide, in the presence of CsF-Celite/acetonitrile and desilylation of (2S)-2-(tert-butyldimethylsilanyloxy)-N-(4-cyano-3-trifluoromethylphenyl)-3-(4-fluorophenoxy)-2,N-dimethylpropionamide in tetra-n-butylammonium fluoride/THF. Both NMR and X-ray analysis confirmed the structure of the 1,4-N→O disubstituted phenyl ring migrated product.     

Fluorocyclohexanes. Part XVII. Dehydrofluorinations of the cis and the trans isomers of 2H-1-(difluoromethyl)decafluorocyclohexane

2H-1-(Difluoromethyl)octafluorocyclohex-1-ene (I) and cobalt trifluoride at 165 °C afforded 2H-1-(trifluoromethyl)octafluorocyclohex-1-ene (IV) and four decafluorocyclohexane derivatives: the cis (III), and trans (V), -2H-1-(trifluoromethyl)-; the cis (VII), and trans (VI), 2H-1-(difluoromethyl) compounds. Dehydrofluorination of VII, using aqueous potassium hydroxide, gave only one alkene, 1-(difluoromethyl)nonafluorocyclohex-1-ene (VIII). In a slower reaction VI afforded two alkenes, mainly VIII, But also an isomer, 1-(difluoromethyl)nonafluorocyclohex-2-ene (IX) (ratio 2:1).     

Synthesis of oligosaccharides as potential novel food components and upscaled enzymatic reaction employing the β-galactosidase from bovine testes

The β-galactosidase from bovine testes (EC 3.2.1.23) promotes the transfer of a galactose unit to glucose or galactose-containing residues in manifold derivatives, establishing β1→3 linkages.The synthesis of several potentially biologically important oligosaccharides β-d-Galp-(1→3)-α-d-Glcp-(1→2)-β-d-Fruf2, β-d-Galp-(1→3)-β-d-Galp-(1→4)-α,β-d-Glcp4, β-d-Galp-(1→3)-α-d-Glcp-(1→4)-d-Glcp-ol/Manp-ol 6, β-d-Galp-(1→3)-α-d-Glcp-(1→6)-β-d-Fruf8, β-d-Galp-(1→3)-α-d-Glcp-(1→6)-[α-d-Glcp-(1↔2)]-β-d-Fruf10, α-d-Galp-(1→6)-[β-d-Galp-(1→3)]-α-d-Glcp-(1↔2)-β-d-Fruf12, β-d-Galp-(1→3)-α-d-Glcp-(1↔2)-β-d-Fruf-(1↔2)-β-d-Fruf14 has been reached in yields between 7 and 44% by implementation of this specific enzyme. In addition, we found that it is feasible to gain high yields without an enzyme-specific buffer and even making upscaled preparation on a gram scale.     

Stereochemical consequence in the elimination of β-hydroxyalkylsilanes: Stereoselective formation of (Z)- and (E)-alkylidene-γ-butyrolactones

Titanium(IV) chloride-mediated reaction of 4,5-dihydro-2-(trimethylsiloxy)-3-(trimethylsilyl)furan (1a) with acetaldehyde gave $\text{diastereomerically pure}$ (3S^*, 1′R^*)-4,5-dihydro-3-(1′hydroxyethyl)-3-(trimethylsilyl)-2(3$\text{H}$)furanone (2a), which afforded selectively either (Z)- or (E)-α-ethylidene-γ-butyrolactone (3a) under proper conditions. Facile isomerization of 2a into $\text{diastereomerically pure}$ (3S^*, 1′R^*)-4,5-dihydro-3-&{1′-(trimethylsiloxy)ethyl}-2(3$\text{H}$)furanone (4) suggests an intriguing stereochemical outcome from 2a to (E)-3a via an enolate of 4.     

Domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylalkylidene)malononitriles: synthesis of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans and a rare case of [1,5] sigmatropic shift of the nitro group

A variety of functionalized 6-(trifluoromethyl)-6H-dibenzo[b,d]pyrans were easily synthesized in good yields under mild conditions by a domino reaction of 3-nitro-2-(trifluoromethyl)-2H-chromenes with 2-(1-phenylethylidene)- and 2-(1-phenylpropylidene)malononitriles. In the latter case, intermediate 7-amino-10-methyl-10-nitro-9-phenyl-6-(trifluoromethyl)-10,10a-dihydro-6H-benzo[c]chromene-8-carbonitriles were isolated as a result of a rare [1,5] sigmatropic shift of the nitro group.     

An efficient synthesis of a hexasaccharide—the repeating unit of the exopolysaccharide from Cryptococcus neoformans serovar A

A general method for the synthesis of 2-xylose or glucuronic acid branched (1→3)-linked mannose oligosaccharides has been developed. As a typical example, the synthesis of the methyl glycoside of β-d-GlcpA-(1→2)-α-d-Manp-(1→3)-[β-d-Xylp-(1→2)-]α-d-Manp-(1→3)-[β-d-Xylp-(1→2)-]α-d-Manp, the repeating unit of the exopolysaccharide from Cryptococcus neoformans serovar A, was achieved in a regio- and stereoselective manner.     

Syntheses, characterization, X-ray crystal structures and emission properties of five oxovanadium(V) complexes with pyridyl/pyrimidyl-pyrazole derived ditopic ligands

Four oxovanadium(V) complexes of heterocycle based ditopic ligands PyPzOAP (N-[amino(pyridin-2-yl)methylidene]-5-methyl-1-(pyridin-2-yl)-1H-pyrazole-3-carbohydrazonic acid), PyPzOAPz (N-[amino(pyrazin-2-yl)methylidene]-5-methyl-1-(pyridin-2-yl)-1H-pyrazole-3-carbohydrazonic acid), PymPzOAP (N-[amino(pyridin-2-yl)methylidene]-1-(4,6-dimethylpyrimidin-2-yl)-5-methyl-1H-pyrazole-3-carbohydrazonic acid) and PyPzCAP (5-methyl-1-(pyridin-2-yl)-N′-[1-(pyridin-2-yl)ethylidene]-1H-pyrazole-3-carbohydrazide) and a binuclear (di-μ-oxo) oxovanadium(V) complex of the ligand PymPzCAP (1-(4,6-dimethylpyrimidin-2-yl)-5-methyl-N′-[1-(pyridin-2-yl)ethylidene]-1H-pyrazole-3-carbohydrazide) have been investigated. The ligands act as uninegative NNO tridentates donors for the VO₂⁺ ion exhibiting their monotopicity. The ligands show varying emission properties due to the presence of fluophoric groups like 1-(2-pyridyl)pyrazole or 1-(2-pyrimidyl)pyrazole. The vanadium(V) complexes show fluorescence quenching with respect to the used ligands to a varying extent. The complexes were characterized by UV-Vis, IR, cyclic voltammetry and X-ray crystallography.     

Synthesis of N-arylcarbamates with tetrazole fragment and some their derivatives

Reactions of methyl(ethyl) N-(2-cyanophenyl)carbamates with sodium azide in dimethylformamide at 80–90°C in the presence of anhydrous CdCl₂ afforded the corresponding N-arylcarbamates with a 1,2,3,4-tetrazole fragment. The acylation of methyl N-[2-(1H-1,2,3,4-tetrazol-5-yl)phenyl]carbamate with acetic anhydride followed by the condensation of the obtained N-acyl derivative with thiophene-2-carbaldehyde in the KOH methanol solution led to the formation of methyl N-(2-{1-[3-(2-thienyl)-2-propenoyl]-1H-1,2,3,4-tetrazol-5-yl}phenyl)carbamate. The reaction of cyclohexyl N-(4-aminophenyl)carbamate with a triethyl orthoformate and sodium azide in glacial AcOH yielded cyclohexyl N-[4-(1H-1,2,3,4-tetrazol-1-yl)phenyl]carbamate.     

Synthesis and oxidation of (E)-1,2-diphenyl-2-(arylimino) ethanol derivatives

The compounds (E)-1,2-diphenyl-2-(phenylimino)ethanol, (E)-1,2-diphenyl-2-(p-tolylimino)ethanol, and (E)-2-((4-chlorophenyl)imino)-1,2-diphenylethanol) were synthesized by reaction of a p-substituted aniline with benzoin then oxidized with chromium trioxide–triethylamine in chloroform to give (E)-1,2-diphenyl-2-(phenylimino)ethanone, (E)-1,2-diphenyl-2-(p-tolylimino)ethanone, and (E)-2-((4-chlorophenyl)imino)-1,2-diphenylethanone in very high yield. The products were characterized by IR and NMR spectral analysis.     

A practical synthesis of enantiopure β-methyltryptophan ethyl ester for a preparation of diabetes drug

A practical synthesis of (2R,3S)- and (2S,3R)-β-methyltryptophan ethyl ester (β-MeTrp-OEt) has been developed. Racemic threo-β-MeTrp-OEt was diastereoselectively prepared via crystallization-induced diastereomer transformation (CIDT) of the α-nitro equivalent of β-MeTrp-OEt. The enantiomers were resolved via diastereomeric salt formation using a half equivalent of (R)-2-(4-hydroxyphenoxy)propionic acid. The process allowed a diabetes drug candidate N-[(1R,2S)-1-({5-[(dimethylamino)methyl]-2-ethoxyphenyl}aminocarbonyl)-2-(1H-indol-3-yl)propyl]-4-phenyl-1-piperidinecarboxamide to be prepared in good yield with high quality.     

Arthrobacter sp.: a lipase of choice for the kinetic resolution of racemic arylazetidinone precursors of taxanoid side chains

The native strain of Arthrobacter sp. (MTCC 5125) bearing a lipase has been found to be the most effective in the kinetic resolution of racemic arylazetidinones for producing cis-(3R,4S)-3-acetoxy-1-(4-methoxyphenyl)-4-phenyl-2-azetidinone, cis-(3R,4S)-3-acetoxy-1-(4-methoxyphenyl)-4-(2-furanyl)-2-azetidinone, cis-(3R,4S)-3-acetoxy-1-(4-methoxyphenyl)-4-(2-thienyl)-2-azetidinone, and cis-3-acetoxy-4-(t-butyl)-2-azetidinone products. The resolved compounds, which were obtained in high enantiopurity are important intermediates of amino acid side chains of paclitaxel as well as a new generation of taxanoids. The use of co-solvents dramatically improved the resolution efficacy of the lipase.     

New chiral phosphine-phosphonites derived from (2R,3R)-dimethyl tartrate, (S)-binaphthol and (1R,2S)-ephedrine

The reaction of 2-lithiophenyldiphenylphosphine with phosphorus trichloride afforded the new unsymmetric phosphine, dichloro(2-diphenylphosphinophenyl)phosphine (4). Condensation of 4 with (a) (2R,3R)-dimethyl tartrate or (b) (S)-binaphthol in the presence of triethylamine gave new chiral phosphine-phosphonite ligands, (2R,3R)-[2-(2′-(diphenylphosphino)phenyl)-4,5-bis(carbomethoxy)-1,3,2-dioxaphospholane] ((2R,3R)-5) and (S)-[2-(diphenylphosphino)benzene][1,1′-binaphthalen-2,2′-diyl]phosphonite] ((S)-6). The analogous reaction of 4 with (1R,2S)-ephedrine using N-methylmorpholine as the base, gave [2-(2′-(diphenylphosphino)phenyl)-3,4-dimethyl-5-phenyl-1,3,2-oxazaphospholidine] (7) as a 95:5 mixture of diastereoisomers.     

Isolation of highly pure erlotinib hydrochloride by recrystallization after nucleophilic substitution of an impurity with piperazine

Optimized synthesis and purification of erlotinib hydrochloride (N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazoline-4-amine hydrochloride) were studied. Highly polar piperazine was used in a nucleophilic substitution reaction with the chlorinated intermediate byproduct N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. As a result, N-(3-ethynylphenyl)-6(2-chloroethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was completely transformed to N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride. The polarity of N-(3-ethynylphenyl)-6(2-piperzinoethoxy)-7-(2-methoxyethoxy)quinazolin-4-amine hydrochloride was changed, and its molecule was enlarged. It was easy to remove this larger, more polar, compound by recrystallization. Highly pure erlotinib hydrochloride was obtained with low impurity content (<1 %). The purity of erlotinib hydrochloride was >99.9 %.     

A practical synthesis of new S,N-disubstituted derivatives of 5-(4-methylpiperidino)methyl-2-thiouracil

5-(4-Methylpiperidino)methyl-2-thiouracil (1) has been obtained via the Mannich reaction between 2-thiouracil, paraformaldehyde, and a cyclic secondary amine such as 4-methylpiperidine (4-MP) in ethanol. New S,N(1)-di-o-(m- and p-)bromo-(nitro-) benzyl-substituted derivatives have been synthesized successfully in the reactions of 1 with the corresponding o-(m- and p-)bromobenzyl bromides or o-(m- and p-) nitrobenzyl chlorides in DMF solution in the presence of K₂CO₃. The opposite method of synthesis, that is, the reaction between 2-o-(m- and p-)bromobenzylthio-1-o-(m- and p-)bromobenzyluracils and 2-o-(m- and p-)nitrobenzylthio-1-o-(m- and p-) nitrobenzyluracils (8), with paraformaldehyde and 4-methylpiperidine in ethanol failed, indicating the important role of the enol form of 2-thiouracil for the Mannich reaction to be successful.     

(R)- and (S)-N-(Benzyloxycarbonyl)-3,4-epoxybutylamine. New 4-amino-2-hydroxybutyl synthons for the synthesis of hypusine reagents and (R)-6- and (S)-7-hydroxyspermidine

The synthesis and application of the chiral reagents (R)- and (S)-N-(benzyloxycarbonyl)-3,4-epoxybutylamine is described for the first time. These 4-amino-2-hydroxybutyl synthons are successfully employed in the assembly of two hydroxylated triamines, (R)-6- and (S)-7-hydroxyspermidine, and a previously described hypusine reagent, (2S,9R)-11-[(benzyloxycarbonyl)amino]-7-(benzyloxycarbonyl)-2-[(9-fluorenylmethoxycarbonyl)amino]-9-(tetrahydropyran-2-yloxy)-7-azaundecanoic acid, useful for solution- and solid-phase peptide synthesis.     

1,5-Stereocontrol in reactions of 2,4-disubstituted alk-2-enylstannanes with aldehydes; an approach to the stereoselective synthesis of branched triols

2-(tert-Butyldimethylsilyloxymethyl)-4-(methoxymethoxy)pent-2-enyl(tributyl)stannane is transmetallated by tin(IV) chloride stereoselectively to give a pent-1-en-3-yltin trichloride that reacts with aldehydes with excellent (E)-1,5-syn-stereocontrol, e.g. (3E)-1,5-syn-3-(tert-butyldimethylsilyloxymethyl)-5-(methoxymethoxy)-1-phenylhex-3-en-1-ol was the dominant product with benzaldehyde. The products from these reactions were taken through to more complex 2-substituted alk-2-enyl(tributyl)stannanes but only very low yields of the expected products were obtained from tin(IV) chloride mediated reactions of these stannanes and aldehydes. Nevertheless a stereoselective synthesis of 2-substituted 4-[(E)-2-alkoxypropylidene]tetrahydrofurans was developed.     

Solid-state electrolytes based on ionic network polymers

Interpenetrating and semi-interpenetrating polymer networks are synthesized with the use of cationic and anionic ionic monomers: N-[3-(methacryloyloxy)propyl]-N-methylpyrrolidinium bis(trifluoromethane-sulfonyl)imide, N-[2-(2-(2-(methacryloyloxy)ethoxy)ethoxy)ethyl]-N-methylpyrrolidinium bis(fluorosulfonyl)imide, and (N-butyl-N-methylpyrrolidinium 1-[3-(methacryloyloxy)propylsulfonyl] (trifluoromethanesulfonyl) imide. Their ionic conductivities, electrochemical stabilities, heat resistances, thermal stabilities, and mechanical properties and the swelling of the films in ionic liquid/lithium salt mixtures were studied. The copolymerization of N-[2-(2-(2-(methacryloyloxy)ethoxy)ethoxy)ethyl]-N-methylpyrrolidinium bis(fluorosulfonyl)imide and poly(ethylene glycol dimethacrylate) and poly(ethylene glycol methacrylate) in the presence of butadiene-acrylonitrile rubber and a solution of Li(CF₃SO₂)₂N in N-(methoxymethyl)-N-methylpyrrolidinium bis(fluorosulfonyl)imide yielded a solid-state electrolyte with a set of properties optimum among the studied films: an ionic conductivity of 1.3 × 10^?4S/cm (25°C), a tensile strength of 80 kPa, and an elongation at break of 60%.