Deoxysugars via microbial reduction of 5-acyl-isoxazolines: application to the synthesis of 3-deoxy-D-fructose and derivatives

5-Acylisoxazolines 3a-d were obtained by 1,3-dipolar cycloaddition from acetoxymethyl vinyl ketone and nitro precursors. Compounds 3a-d were biotransformed by Aspergillus niger into a 1:1 mixture of stereomers of 5-dihydroxyethyl isoxazolines (+)-4a-d (anti) and (-)-5a-d (syn). Both stereomers were obtained in good yields and with high optical purities. Carbonyl reduction by Aspergillus niger produces alcohols of R-configuration thus giving an access to D-sugar analogues: Compound (+)-4d was converted to 3-deoxy-D-erythro-hexulose and several protected derivatives. Total synthesis of 3-deoxy-D-fructose-6-phosphate was also achieved in two steps and 64% overall yield from (+)-4d.     

Synthesis of Spirocyclic and Fused Isoxazoline Building Blocks

A highly efficient multigram synthesis of spirocyclic and fused isoxazoline building blocks is described. Isoxazoline-3-carboxylates were synthesized via a regioselective 1,3-dipolar cycloaddition reaction of 2-chloro-2-(hydroxyimino)acetate and carbo- or heterocyclic alkenes bearing endo- or exocyclic C=C double bonds, resulting in fused or spirocyclic isoxazolines, respectively. The preparation of up to 300 g of these compounds was achieved in a single run. The ester group of isoxazolines was then subjected to common synthetic transformations for the synthesis of corresponding building blocks, including alcohols, chlorides, azides, amines, aldehydes, carboxylic acids, amino acids and their derivatives, difluoromethyl-substituted compounds, and bicyclic γ-lactones. Additionally, a direct cycloaddition-based approach to the synthesis of aminoalkyl- and chloromethyl-substituted isoxazolines was proposed to improve their preparation. The described isoxazoline building blocks are expected to be valuable tools for drug discovery.     

Synthesis and Characterization of Some Novel Higher C,N-Diphenyl Nitrones,Isoxazolines, and Mercaptobenzimidazoles as Oleochemicals

Abstract

Some novel long-chain nitrones, isoxazolines, and (1H-benzo[d]-imidazol-2-ylthio) derivatives were synthesized. Nitrones, N-{4-[2-(tetradecylthio)acetoxy]benzylidene}aniline oxide, and N-[4-(12-oxo-2,5,8,11-tetraoxadocosan-22-yloxy)benzylidene]aniline oxide were prepared via the reaction of β-phenylhydroxylamine with the corresponding aromatic aldehydes. The isoxazolines were prepared from undec-10-en-1-ol and benzonitrile-N-oxide which was generated in situ. The 1H-benzo[d]-imidazol-2-ylthio derivatives were synthesized via the replacement reaction of ω-bromo esters and 2-mercaptobenzimidazole.     

Solid Phase Synthesis of Isoxazole and Isoxazoline-carboxamides via [2+3]-Dipolar Cycloaddition Using Resin-bound Alkynes or Alkenes

An efficient approach for the parallel solid phase synthesis of isoxazole and isoxazoline derivatives has been developed. The isoxazoles and isoxazolines were constructed through a 1,3-dipolar cycloaddition reaction of nitrile oxides, with resin-bound alkynes or alkenes. The cycloaddition reaction conditions performed on solid phase supports was optimized, and an array of resin bound carboxylic acid building blocks were utilized for distinct conversions. This methodology presents a new alternative to the diversity oriented synthesis of disubstituted isoxazoles and isoxazolines different from existing routes which are limited in structural diversity.     

Synthesis and structural characterization of glucopyranosylamide films on gold

Self-assembled monolayers (SAMs) of glucose derivatives on gold have been prepared from alpha- and beta-glucopyranosylamide derivatives. The glucosyl conjugates were synthesized stereoselectively via the in situ generation of glucosyl isoxazolines followed by treatment with thiopyridyl esters. The resulting film structures were characterized by atomic force microscopy, reflection Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The experimental data indicated that alpha- or beta-linked glucopyranosylamide derivatives with free hydroxyl groups attach to gold via the thiol linker. Both derivatives form monolayer films with high packing densities--comparable to those typically observed for alkanethiol monolayers on gold. Acetate analogues of these conjugates do not form SAMs on gold; they form multilayered films under identical deposition conditions.     

A new route to the synthesis of isoxazoline derivatives from dihydropyran via cycloaddition reaction in ionic liquid

A new approach to the synthesis and 1,3-dipolar cycloadditions of nitrones has been described from 2,3-dihydro-4H-pyran and various hydroxylamines, with electron-deficient alkynes for the synthesis of isoxazoline derivatives. Significant rate acceleration and improved yields of exclusively exo isoxazolines in 1-butyl-3-methylimidazolium based ionic liquids have been observed. Novel isoxazolines may be used as a precursor for the synthesis of variety of peptides.     

Synthesis of isoxazolines from nitrile N-oxides generated from nitroalkenes

In this review, information on the production of isoxazolines and condensed isoxazoline systems by the intramolecular 1,3-bipolar cycloaddition of unsaturated nitrile N-oxides generated in situ from nonconjugated nitroalkenes is generalized and systematized. The isoxazoline derivatives formed as the result of these reactions are promising synthons in the synthesis of various natural compounds and their analogues.Krakow Polytechnic Institute, Poland. Translated from Khimiya Prirodnykh Soedinenii, Nos. 3,4, pp. 291–305, May–August, 1992.     

Synthesis and properties of azoles and their derivatives

The 1,3-dipolar cycloaddition reaction of nitrile N-oxides, and also the thermal condensation of arylhydroxamic acid chlorides with unsaturated derivatives of the adamantane series leads to the corresponding 3,5-disubstituted isoxazolines and isoxazoles.     

1,3-Dipolar cycloaddition reactions of 4-arylidene-2-phenyl-1,4-dihydroimidazol-5-ones with nitrile oxides

Stable nitrile oxides add regioselectively to the carbon-carbon double bond of 4-arylidene-2-phenyl-1,4-dihydroimidazol-5-ones to afford spiro isoxazolines 3 . Compounds 3 are further hydrolysed to isoxazole derivatives.     

Isoxazoline derivatives from activated primary nitrocompounds and tertiary diamines

Activated nitrocompounds, in the presence of dipolarophiles and a tertiary diamine (e.g., DABCO), undergo dehydration to afford directly isoxazoline derivatives, formal cycloadducts of nitrile oxides; this mild procedure is very efficient for the synthesis of the reported isoxazolines.     

A Simple,Efficient One‐Pot Synthesis of 2‐Isoxazoline Derivatives and their Antimicrobial Activity

Synthesis of substituted 2‐isoxazolines derivatives with sulfone functional groups was accomplished by 1,3‐dipolar cycloaddition reaction. The 1,3‐dipolar nitrile oxides generated in situ by reacting α‐formaldoximes with N‐bromosuccinimide in the presence of triethylamine on reaction with activated alkenes in toluene at room temperature afford the corresponding 2‐isoxazolines in high yields. All the 2‐isoxazoline derivatives were assayed for their antibacterial activities against Staphylococcus aureus, Bacillus cereus, Escherichia coli, and Pseudomonas aeruginosa and antifungal activities against Aspergillus niger and Candida albicans. Most of the compounds showed good antibacterial and antifungal activities.     

Water‐Assisted Nitrile Oxide Cycloadditions: Synthesis of Isoxazoles and Stereoselective Syntheses of Isoxazolines and 1,2,4‐Oxadiazoles

Conventional methods generate nitrile oxides from oxime halides in organic solvents under basic conditions. However, the present work revealed that water‐assisted generation of nitrile oxides proceeds under mild acidic conditions (pH 4–5). Cycloadditions of nitrile oxides with alkynes and alkenes easily occurred in water without using catalysts, thus yielding isoxazoles and isoxazolines, respectively, with excellent stereoselectivity toward five‐ and six‐membered cyclic alkenes. A double stereoselective cycloaddition of two units of a nitrile oxide with cyclohexene was also achieved, thus yielding 1,2,4‐oxadiazole derivatives having a unique hybrid isoxazoline‐oxadiazole skeleton. Enantiomerically pure isoxazolines were prepared from monoterpenes with a ring strain. In one case, the isoxazoline with a butterfly‐like structure was simply prepared, and it might be used as a ligand in asymmetric catalysis.     

Reaction of hydroxylamine with 5-aminooxazoles. A new route to isoxazoles

The nucleophilic attack of hydroxylamine at the 5 position of 2-aryl-4-trifluoroacetyl-5-amino-oxazoles leads to a mixture of stereoisomeric isoxazolines. Dehydration of these isomeric isoxazolines in the presence of trifluoroacetic anhydride gives 3-amino-4-acylamino-5-trifluoromethylisoxazoles. The structures and spectroscopic data of these compounds are discussed.     

Asymmetric Synthesis of Agrochemically Attractive Trifluoromethylated Dihydroazoles and Related Compounds under Organocatalysis

The unique, partially saturated, fluorinated five‐membered heterocyclic compounds, trifluoromethylated dihydroazoles, and their derivatives, have emerged as a new class of heterocycles with remarkable biological activities in the 21st century. Despite their small molecular structures, a single sterically demanding tetrasubstituted trifluoromethylated stereogenic carbon center has prevented chemists from achieving the asymmetric synthesis of these compounds. In this account, we describe our recent progress in the catalytic asymmetric synthesis of a series of trifluoromethylated heterocycles, such as isoxazolines and pyrrolines having a stereogenic carbon center, based on organocatalysis. Our protocols have advantages in terms of employing inexpensive reagents and organocatalysts and they would be useful for industrial production.     

One-pot Synthesis of Isoxazolines Using Soluble Polymer-supported Acrylates

An efficient and rapid parallel liquid-phase synthesis of isoxazolines has been reported.The one-pot three-component reaction of polyethylene glycol-supported acrylates, aldehydes and hydroxylamine hydrochloride in the presence of chloramine-T in methanol gave the corresponding PEG-supported isoxazolines, which can be cleaved from the support under mild condition to afford isoxazolines in good yields (＞80%) and high purities (＞86%).     

Stereochemically rich pentaketides from bis(isoxazolines): a general strategy for efficient polyketide synthesis

[reaction: see text] A strategy based on diastereoselective dipolar cycloaddition reaction of nitrile oxides and allylic alcoholates has been applied to the synthesis of bis(isoxazolines) that are precursors to polyketide fragments. These intermediates can be elaborated into protected polyols by chemoselective reductive opening of each isoxazoline sequentially or, alternatively, both simultaneously, potentially providing access to all stereoisomers of this carbon skeleton.     

An approach to lankacidin synthesis: control of stereochemistry using Δ2-isoxazolines

A procedure is developed for the 'one-pot' acylation and methylation of isoxazolines at C(4). Thus the 5-substituted isoxazolines (8), (9), and (18) were converted into their $\text{cis}$-4-methoxycarbonyl-$\text{trans}$-4-methyl derivatives (10), (11), and (19), by deprotonotion using lithium diisopropylamide, followed by the sequential addition of methyl chlorofonmate and methyl iodide. The reduction of these substituted isoxazolines was then investigated. $\text{N}$-Methylation using Meerwein's salt, and reduction of the derived $\text{N}$-methylisoxazolinium salt using sodium borohydride gave isoxazolidines (14) and (20), but only in modest yields. The analogous $\text{N}$-methylation - reduction of the lactone-isoxazoline (12) was not stereoselective. The isoxazolidines (14) and (20) have the correct relative configurations at C(3) and C(4) for conversion into lankacidin analogues.     

Oxazole and Isoxazole Chemistry in Crop Protection

An overview is given of the significance of the oxazole and isoxazole scaffolds in crop protection chemistry. The main herbicidally, fungicidally, and insecticidally active oxazole and isoxazole classes are presented, together with their synthesis routes, modes of action, and biological efficacies. In addition, the role of oxazoles and isoxazoles as lead structure or as intermediate in the synthesis of other agrochemicals is reported. Also, partially and fully saturated oxazole and isoxazole derivatives such as oxazolines, isoxazolines, oxazolidines, and isoxazolidines, oxygenated derivatives such as oxazolones and isoxazolones as well as annulated derivatives, such as benzoxazoles and benzisoxazoles, are covered.     

An efficient one-step regiospecific synthesis of novel isoxazolines and isoxazoles of N-substituted saccharin derivatives through solvent-free microwave-assisted [3+2] cycloaddition

Novel isoxazolines and isoxazoles of N-substituted saccharin derivatives are synthesized in good yields by 1,3-dipolar cycloaddition of N-allyl or propargyl N-substituted saccharin with arylnitrile oxide under solvent-free microwave irradiation. In this process, the yields were significantly improved over conventional heating, without alteration of the selectivity. The regioselectivity as well as the nonthermal specific microwave effect are discussed.     

Hypervalent iodine-mediated interaction of aldoximes with activated alkenes including Baylis-Hillman adducts: a new and efficient method for the preparation of nitrile oxides from aldoximes

Treatment of aldoximes with activated alkenes in the presence of diacetoxy iodobenzene (DIB) afforded isoxazolines in high yields. The method has been applied for the preparation of polyfunctional isoxazolines from Baylis-Hillman adducts.