Efficient approach to the unknown isoxazolo[3,4-d]thieno[2,3-b]pyridine system by regioselective intramolecular nitrone cycloadditions

An effective approach to the new isoxazolo[3,4-d]thieno[2,3-b]pyridine system was provided by way of an intramolecular nitrone cycloaddition. The required nitrones were built in good yields starting from thiophene-2-carboxylic acids. The same skeleton was achieved in optically active form employing chiral nitrones derived from N-α-methylbenzyl- and the N-α-hydroxymethylbenzyl-hydroxylamines. The absolute configuration of the products was assigned by X-ray analysis.     

Alkynylation of N-tosylimines with aryl acetylenes promoted by ZnBr2 and N,N-diisopropylethylamine in acetonitrile

We found a suitable condition for the effective alkynylation of N-tosylimines with aryl acetylenes. The reaction of N-tosylimines and aryl acetylenes in the presence of ZnBr₂ and DIEA (N,N-diisopropylethylamine) in CH₃CN afforded the desired N-tosyl propargylamines in moderate to good yields.     

Experimental and theoretical studies on Mannich-type reactions of chiral non-racemic N-(benzyloxyethyl) nitrones

The nucleophilic addition of both silyl ketene acetals and lithium enolates derived from methyl acetate to chiral non-racemic N-(benzyloxyethyl)nitrones has been studied both experimentally and theoretically. Aromatic nitrones showed lower reactivity that aliphatic nitrones and the addition of the silyl ketene acetal led to lower selectivities than the addition of the corresponding lithium enolate. Whereas low selectivity was obtained for the addition of the silyl ketene acetal, only one diastereomer could be detected in all cases for the addition of lithium enolate to aliphatic nitrones. The synthetic utility of the two chiral auxiliaries employed lies in the preparation of enantiomeric compounds. DFT theoretical calculations confirmed the stepwise mechanism for the addition of silyl ketene acetals to nitrones and are in good agreement with the observed experimental results.     

Facile and convenient synthesis of functionalized propargylic alcohols and amines: an InBr3-Et3N reagent system promotes the alkynylation of aldehydes and N,O- or N,S-acetals

The use of a novel InBr₃-Et₃N reagent system to promote the alkynylation of not only a variety of aromatic/heterocyclic or bulky aliphatic aldehydes but also N,O- or N,S-acetals is described. The use of N-silyl-N,O-acetals and 1-alkynes could lead to the direct production of primary propargylic amines in good yields.     

Chiral N-phosphonyl imine chemistry: asymmetric 1,2-additions of allylmagnesium bromides

Chiral N-phosphonyl homoallylic amines were synthesized by the reaction of allylmagnesium bromide with chiral N-phosphonyl imines. The C₂-symmetric chiral N-phosphonyl group was optimized for this reaction. Excellent yields and good diastereoselectivities were obtained for eight examples.     

Silyl triflate-accelerated additions of catalytically generated zinc acetylides to N-phenyl nitrones

Terminal alkynes readily form zinc acetylides in the presence of iPr₂NEt and 20 mol % ZnBr₂, then attack N-phenyl nitrones activated by trimethylsilyl trifluoromethanesulfonate. Deprotection with aqueous acid yields N-hydroxyl propargylamine. Yields are generally high for nitrones derived from aromatic aldehydes. Control experiments suggest that silyl triflate has a significant accelerating effect upon the reaction.     

Practical preparation of N-(1-alkynyl)sulfonamides and their synthetic utility in titanium alkoxide-mediated coupling reactions

Aliphatic and aromatic sulfonamides were alkynylated with 1-bromo-1-alkynes in the catalytic presence of CuI to give N-(1-alkynyl)sulfonamides in good to excellent yields. Racemization of optically active sulfonamides was not observed during this alkynylation. The acetylene-titanium complexes generated from the resultant N-(1-alkynyl)sulfonamides and Ti(O-i-Pr)₄/2 i-PrMgCl underwent regio-, olefinic stereo-, and diastereoselective addition to aldehydes to give virtually single allyl alcohols. Alternatively, inter- or intramolecular coupling reaction between N-(1-alkynyl)sulfonamides and another acetylene or olefin with the above titanium alkoxide reagent generated the corresponding titanacycles, hydrolysis of which furnished stereo-defined (sulfonylamino)dienes or cyclic compounds.     

Synthesis of chiral sultams and their application as chiral auxiliaries in an asymmetric Diels–Alder reaction

A number of bicyclic chiral sultams were synthesized based on 1,3-dipolar cycloaddition reactions of nitrile oxides and nitrones with prop-1-ene-1,3-sultone. The corresponding N-enoyl sultams were prepared by acylation. Their relative effectiveness as new chiral auxiliaries in asymmetric synthesis was evaluated for the asymmetric Diels–Alder reactions with cyclopentadiene. Good chemical yield and excellent endo selectivity were observed. The relationship between the structure and their effectiveness in promoting asymmetric induction of the synthetic chiral sultams was investigated.     

Increased formation of oxepanes in non-aqueous medium in the cycloaddition of 3-O-allyl-1,2-isopropylidenefuranose N-Ph nitrones

Cycloaddition of 3-O-allyl-1,2-isopropylidene N-Ph nitrones afforded appreciably increased yields of oxepanes compared to the corresponding N-Me or N-Bn nitrones. Higher yields permitted some useful further transformations of the oxepanes.     

Design and synthesis of a tridentate ligand inspired by the phenomenon of self-assembly catalysis and its application in the asymmetric alkynylation of N-(diphenylphosphinoyl) imines

On the basis of the phenomenon of self-assembly catalysis, a tridentate ligand was designed and synthesized in two steps. The application in alkynylation of N-(diphenylphosphinoyl) imines gave the expected products. Aromatic, heteroaromatic N-(diphenylphosphinoyl) imines were employed and gave optically active propargylic amines in good yields (up to 89%) and excellent enantioselectivities (up to 96%) by a simple experimental procedure. The direct use of sulfone amides in the alkynylation of N-(diphenylphosphinoyl) aliphatic imines made this method very attractive.     

Enantioselective synthesis of homocarbocyclic-2′-oxo-3′-azanucleosides

The enantioselective synthesis of homocarbocyclic-2′oxo-3′-azanucleosides has been performed by cycloaddition reaction of the N-glycosyl nitrones with allyl nucleobases. The use of nitrones originated from two different carbohydrates, the N-ribosyl nitrone and the N-mannosyl nitrone, proceeded in a stereocontrolled and predictable manner with a good degree of enantioselectivity, so allowing an easy entry to both enantiomers.     

Synthesis and application of <Emphasis Type="Italic">N</Emphasis>-hydroxy(tetrahydrofuran-2-yl)amines

Data on synthesis, reactivity and bioactivity of N-hydroxy(tetrahydrofuran-2-yl)amines were discussed in the present review. General approaches to chiral N-glycosylhydroxylamines based on reactions of hydroxylamine with cyclic five-membered hemiacetals or dihydrofurans as well as reactions of tetrahydrofuran-containing nitrones with nucleophiles were systematized. The application of N-hydroxy(tetrahydrofuran-2-yl)amines in the synthesis of chiral heterocycles, aminophosphonic acids, N-hydroxypropargylamines, as well as natural compounds (for example, sieboldin A), pharmaceuticals (Zileuton) and their analogs was demonstrated. It was found that depending on substituents, N-hydroxy(tetrahydrofuran-2-yl)-amines can act as lipoxygenase inhibitors, and show antioxidant, antitumor, antibacterial, and other types of activities.     

Stereoselective 1,3-dipolar cycloadditions of nitrones derived from amino acids. Asymmetric synthesis of N-(alkoxycarbonylmethyl)-3-hydroxypyrrolidin-2-ones

Diastereoselective asymmetric 1,3-dipolar cycloadditions of N-(alkoxycarbonylmethyl) nitrones derived from glycine, alanine and phenylalanine have been studied both experimentally and theoretically. Asymmetric induction is evaluated by either introducing a chiral group at the nitrone nitrogen atom or by using Oppolzer's sultam acrylamide. In both cases the sense of the asymmetric induction is the same, the (3R,5R)-isomer being preferentially obtained. The best results were observed with the chiral dipolarophile, which afforded an only isomer in all cases. The obtained isoxazolidines are easily transformed into the corresponding 5-substituted-3-hydroxypyrrolidin-2-ones. DFT studies are in a qualitative agreement with the observed experimental results.     

Indium-mediated alkynylation of Baylis-Hillman acetates: a novel route to 1,4-enynes

Baylis-Hillman acetates undergo smooth alkynylation with aryl-susbstituted iodoalkynes in the presence of indium metal in refluxing dichloromethane to furnish 1,4-enynes in high yields with (E)-stereoselectivity. In the absence of Lewis acid, the reaction follows both S_N2 and S_N2′ pathways affording 1:1 mixtures of 1,4-enynes. Upon addition of 10 mol % of InBr₃, the reaction proceeds preferably in the S_N2′ manner. In the case of adducts derived from acrylonitrile, the corresponding products are obtained in fairly good yields and with (Z)-stereoselectivity.     

Copper(I)-Catalyzed Highly Enantioselective [3+3]-Cycloaddition of β-Aryl/Alkyl Vinyl Diazoacetates with Nitrones

β-Aryl/alkyl vinyl diazoacetates were investigated in metallo-vinylcarbene reactions with nitrones, revealing a Rh₂(OAc)₄-catalyzed cyclopropene dimerization reaction and a copper(I) catalyzed [3+3]-cycloaddition of nitrones. The chiral cyclopropyl-In-SaBox ligand with copper(I) catalysis could realize the asymmetric version of the cycloaddition reaction, delivering various 3,6-dihydro-1,2-oxazine derivatives in good yield and with excellent enantioselectivity under mild conditions.     

Asymmetric O-methylhalohydrin reaction of chiral N-enoyl-2-oxazolidinones: synthesis of N-protected syn-β-methoxyphenylalanine, an unusual amino acid component of cyclomarins

Asymmetric O-methylhalohydrin reactions of chiral N-enoyl-2-oxazolidinones were performed with halogens (Br₂/I₂) promoted by silver(I) in methanol with high regio- and anti-selectivity and moderate to good diastereoselectivity. Reagent-controlled opposite diastereoselectivity was observed especially for cinnamoyl and electron-deficient cinnamoyl substrates. This method was applied to the short enantioselective synthesis of N-protected syn-β-methoxyphenylalanine, an unusual amino acid component of cyclomarins.     

Sulfoxide-controlled SN2′ displacements between cuprates and vinyl and alkynyl epoxy sulfoxides

The S_N2′ displacement of readily available vinyl epoxy sulfoxides with organocopper reagents takes place in good yields with high anti selectivity and a good degree of E/Z stereocontrol to produce enantiopure α-hydroxy vinyl sulfoxides. A second allylic displacement on the related mesyloxy vinyl sulfoxides allows for the asymmetric construction of two adjacent chiral centers. In addition, cuprate mediated S_N2′ addition to alkynyl epoxy sulfoxides affords α-hydroxy allenyl sulfoxides in good yields.     

A novel fluorescent enantioselective discrimination of lansoprazole based on a chiral N,N′-dioxide-Sc(III) complex

A good chiral discrimination of lansoprazole (LAN) enantiomers was realized by a chiral N,N′-dioxide-Sc(III) complex, which was based on a fluorescent method through an ‘off-on’ process. The chiral ligand, N,N′-dioxide, coordinated with scandium(III) triflate forming an organic-metal complex as a chiral selector. Then the LAN enantiomers reacted with the selector and generated different signals in fluorescence. A distinct enantiomeric difference was observed with good repeatability, low detection limit, good linear range, and highly enantiomeric selectivity. At last, this study had offered a quantitative measurement of the enantiomer composition.     

Catalytic asymmetric addition of arylboronic acids to N-Boc imines generated in situ using C2-symmetric cationic N-heterocyclic carbenes (NHCs) Pd diaquo complexes

The catalytic asymmetric addition of arylboronic acids to N-Boc imines generated in situ from stable and easily prepared α-carbamoyl sulfones was realized by using chiral cationic C₂-symmetric N-heterocyclic carbene (NHC) Pd²⁺ diaquo complexes 1a-c as the catalysts, producing the corresponding adducts in good to high yields (up to 89%) and good to high enantioselectivities (up to 90% ee).     

Asymmetric cyanosilylation of ketones catalyzed by novel chiral N,N′-dioxide titanium complexes

A novel C₂-symmetric chiral N,N′-dioxide titanium complex was described, which could efficiently catalyze the asymmetric cyanosilylation of ketones in high yields with up to 92% ee under mild conditions. In addition, the catalyst system was simple and the ligands could be easily prepared from commercially available chiral amino acid.