Intramolecular Nitrone Research Articles

Diastereoselective 1,3-dipolar intramolecular nitrone olefin cycloaddition (INOC) reaction of a sugar-derived allyl alcohol: Synthesis of functionalized aminocyclopentitols

The DIBAL-H reduction of the Baylis-Hillman sugar adduct, obtained from 3-O-benzyl-1,2-isopropylidene-α-D-xylo-pentodialdo-1,4-furanose yielded trisubstituted alkenes by eliminating the β-hydroxyl group. Subsequently, the hydrolysis of the isopropylidene acetal to the corresponding hemiacetal was reacted with N-benzyl hydroxylamine hydrochloride to generate the nitrone, which underwent diastereoselective intramolecular 1,3-dipolar nitrone olefin cycloaddition (INOC) to give an isoxazolidine skeleton. The concomitant reductive cleavage of the N-O bond and benzyl group of the fused isoxazolidines afforded new functionalized aminocyclopentitols in good yields.

Intramolecular Nitrone Interrupted Click Reaction.

We document the intramolecular interception of a Cu-catalyzed azidoalkyne cycloaddition employing a suitably placed nitrone group, providing a simple route to the unprecedented spiro-polyheterocyclic scaffold. The reaction is comprised of a Cu-catalyzed [3 + 2]-cycloaddition of (2-azidoaryl)isatogen with a terminal alkyne and the intramolecular trapping of the transient Cu-triazolide intermediate with the isatogen, with a net formation of one C-C and two C-N bonds and the new heterocyclic ring being spiro-annulated.

Total Synthesis of (±)-Thebainone A by Intramolecular Nitrone Cycloaddition.

Using an intramolecular nitrone cycloaddition and a Heck cyclization as the crucial transformations, a total synthesis of the racemic morphine alkaloid thebainone A was accomplished in 22 steps commencing with isovanillin.

Diastereoselective catalyst-free construction of isoxazolidine-cis-fused phospha dihydrocoumarins via an intramolecular Nitrone–Vinylphosphonate dipolar cycloaddition

An efficient stereoselective method towards the construction of isoxazolidine-cis-fused phosphadihydrocoumarins frameworks involving an intermolecular 1,3-dipolar nitrone cycloaddition reaction utilizing O-vinylphosphonylated salicylaldehydes and N-substituted hydroxylamines in situ formation of Nitrone–Vinylphosphonate bifunctional intermediates under catalyst free condition have been described.

Cascade cyclization and intramolecular nitrone dipolar cycloaddition and formal synthesis of 19-hydroxyibogamine.

A cascade or domino sequence of condensation of hydroxylamine and an aldehyde to give an oxime, cyclization to a nitrone, and intramolecular 1,3-dipolar cycloaddition has been successfully employed where there is branching at C-4 as a route to the iboga alkaloids. Cyclization occurs with displacement of chloride as a leaving group and intramolecular cycloaddition occurs with an alkene as a dipolarophile. The reaction gives an azabicyclo[2.2.2]octane product containing a fused isoxazolidine as a single stereoisomer and this was converted to an isoquinuclidine that completed a formal synthesis of the alkaloid (±)-19-hydroxyibogamine.

Formal Synthesis of (-)-Codeine by Application of Temporary Thio Derivatization.

Desymmetrization of a p-quinone monoacetal by organocatalytic sulfa-Michael addition provided rapid access to a C-ring building block for a formal synthesis of (-)-codeine. By means of a diastereoselective 1,2-addition for A/C-ring union, an intramolecular nitrone cycloaddition for construction of the phenanthrene core, and a sulfoxide elimination, an enantiopure key intermediate of the authors' previous synthesis of racemic codeine was available in 12 steps from isovanillin.

Biomimetic Total Syntheses of Clavine Alkaloids.

Biomimetic total syntheses of either enantiomers of a number of ergot alkaloids, chanoclavine I (1b), chanoclavine I aldehyde (1c), pyroclavine (1e), festuclavine (1f), pibocin A (1g), 9-deacetoxyfumigaclavine C (1h), and fumigaclavine G (1i), have been achieved from seco-agroclavine (1a). The advanced intermediate for seco-agroclavine (1a) was synthesized via a key thiourea-catalyzed intramolecular nitronate addition onto α,β-unsaturated ester.

Organocatalytic Enantioselective Synthesis of Trifluoromethyl‐Containing Tetralin Derivatives by Sequential (Hetero)Michael Reaction–Intramolecular Nitrone Cycloaddition

AbstractThe enantioselective synthesis of tetralin derivatives bearing a trifluoromethylated all‐carbon quaternary stereocenter has been accomplished through a synthetic sequence comprising an organocatalytic β‐functionalization of ortho‐1‐trifluoromethylvinyl‐(hetero)aromatic conjugated aldehydes followed by the intramolecular nitrone 1,3‐cycloaddition reaction (INCR). Both nitromethane and N‐Cbz‐hydroxylamine were employed as nucleophiles in the initial organocatalytic conjugate addition step, which provided the chiral information required for the subsequent diastereoselective INCR. Although diastereoselectivity was moderate, good yields and enantioselectivities were, in general, obtained. Interestingly, an inversion of the selectivity in the intramolecular cycloaddition step was observed when either nitromethane or N‐Cbz‐hydroxylamine was employed. This outcome was studied by means of theoretical calculations, which were in agreement with the experimental results. In addition, the ring opening of the isoxazolidine moiety furnished the corresponding fluorinated diamino alcohols in a very efficient manner.magnified image

Total Syntheses of Pyroclavine, Festuclavine, Lysergol, and Isolysergol via a Catalytic Asymmetric Nitro-Michael Reaction.

A catalytic enantioselective construction of vicinal stereocenters is reported. The reaction takes advantage of thiourea-catalyzed intramolecular nitronate addition onto α,β-unsaturated ester to afford exceptional levels of enantioselectivity (up to 97 % ee) with moderate diastereoselectivity (up to 4:1). Using this method, a cross-conjugated ester was synthesized in few steps, from which a 6-endo-trig cyclisation led to the formation of all required functionalities for total syntheses of ergot alkaloids. The strategy not only offers first total syntheses of ergot alkaloids, festuclavine (1 c), and pyroclavine (1 e), and but also an efficient and general approach to other congeners such as, lysergol (1 b), and isolysergol (1 d).

Intramolecular Nitrone Cycloaddition of α-(Trifluoromethyl)styrenes. Role of the CF3 Group in the Regioselectivity.

The intramolecular 1,3-dipolar cycloaddition of ortho-substituted 1,1,1-trifluoromethylstyrene-derived nitrones is described. Tricyclic fused isoxazolidines were obtained as major or exclusive products, in contrast to the case for nonfluorinated substrates, which rendered the bridged derivatives. This change in the regioselectivity was attributed to the electronic and, particularly, steric requirements of the trifluoromethyl group in comparison to the methyl group. It is worth mentioning that trifluoromethylstyrenes have been employed for the first time as dipolarophiles in a 1,3-dipolar intramolecular cycloaddition reaction, leading to the corresponding isoxazolidines bearing a quaternary trifluoromethyl moiety. Finally, the synthetic utility of the developed methodology has been illustrated with the synthesis of a family of bicyclic fluorinated 1,3-amino alcohols.

ChemInform Abstract: Diastereoselective Construction of Highly Functionalized Tetrahydroquinolinoisoxazole Scaffolds via Intramolecular Nitrone Cycloaddition.

AbstractA diastereo‐ and regioselective construction of tetrahydroquinolinoisoxazoles (III) and (V) is achieved by reaction of Baylis—Hillman derivatives (I) and (IV) with N‐alkylhydroxylamine hydrochlorides.

Preparation of a 1,2-isoxazolidine synthon for the synthesis of zetekitoxin AB

A synthesis of the 1,2-isoxazolidine fragment of the potent voltage gated sodium channel blocker, zetekitoxin AB is described. The synthesis utilizes an intramolecular nitrone–olefin 1,3-dipolar cycloaddition to establish the stereochemistry of the cis-1,2-isoxazolidine. The oxidative cleavage of an all anti-triol with the excision of the central carbon is central to using α-d-glucopyranoside as a traceless stereochemical template. This route furnishes a suitably protected synthon for the synthesis of zetekitoxin AB.

Diastereoselective construction of highly functionalized tetrahydroquinolinoisoxazole scaffolds via intramolecular nitrone cycloaddition

A novel strategy towards the construction of highly diversified tetrahydroquinolinoisoxazole frameworks with high diastereoselectivity via intramolecular 1,3-dipolar nitrone cycloaddition reaction is described for the first time. All the synthesized tetrahydroquinolinoisoxazoles are new and obtained in excellent yields under catalyst free condition.

Synthesis of Isoxazolidine-Fused Eight-Membered Heterocycles via an Intramolecular Nitrone–Alkene Cycloaddition

An intramolecular nitrone–alkene cycloaddition yielded novel tricyclic eight-membered ring with a cis-fused isoxazolidine in good to excellent yields under mild reaction conditions.

ChemInform Abstract: A Tactical Approach for the Synthesis of Novel β‐Lactam‐Substituted, Polycyclic‐Fused Isoxazolidine Derivatives via an Intramolecular [3 + 2] Cycloaddition Reaction.

Abstract The synthesis of functionalized β-lactam-substituted, tricyclic chromenoisoxazolidine and tetracyclic naphthopyranoisoxazolidine derivatives by intramolecular nitrone cycloaddition reaction is described. The O-allyl hydroxyaldehyde derivatives, obtained from Baylis–Hillman adducts (BHA) derived from β-lactam aldehyde underwent intramolecular cycloaddition reaction to give β-lactam-substituted, polycyclic isoxazolidine derivatives in good yield. All the products were confirmed by spectral analysis. The products with a β-lactam substituent may find good applications in biological chemistry.

A tactical approach for the synthesis of novel β-lactam-substituted, polycyclic-fused isoxazolidine derivatives via an intramolecular [3+2] cycloaddition reaction

The synthesis of functionalized β-lactam-substituted, tricyclic chromenoisoxazolidine and tetracyclic naphthopyranoisoxazolidine derivatives by intramolecular nitrone cycloaddition reaction is described. The O-allyl hydroxyaldehyde derivatives, obtained from Baylis–Hillman adducts (BHA) derived from β-lactam aldehyde underwent intramolecular cycloaddition reaction to give β-lactam-substituted, polycyclic isoxazolidine derivatives in good yield. All the products were confirmed by spectral analysis. The products with a β-lactam substituent may find good applications in biological chemistry.

Synthesis of new chromeno-annulated cis-fused pyrano[4,3-c]isoxazole derivatives via intramolecular nitrone cycloaddition and their cytotoxicity evaluation

New cis-fused chromeno pyrano[4,3-c]isoxazole derivatives have been synthesized by intramolecular [1,3]-cycloaddition of the nitrones generated in situ from hydroxylamine derivatives and 7-O-prenyl derivatives of 8-formyl-2,3-disubstituted chromenones using PEG-400 as a reaction medium under catalyst-free conditions good to excellent yields. The structures were established by spectroscopic data and further confirmed by X-ray diffraction analysis. The results showed that compounds 4b, 4c, 4d, 4e and 4k exhibit very potent antiproliferative activity against MDA-MB-231 breast cancer cells. Compounds 4a, 4c, 4e, 4i and 4k displayed potent inhibitory activity against human MCF-7 breast cancer cell lines. Compounds 4h and 4i exhibited significant anti-proliferative activity against human cervical cancer cell line, HeLa. While 4b, 4d and 4j were active against human lung cancer cell line, A549. In addition, Compound 4j was found to be the most promising against A549 (Lung cancer) with IC50 value of 0.194μM.

Enantiodivergency and Enantioconvergency in the Synthesis of the Dendrobate Alkaloid 241D

A diastereodivergent preparation of two N-alkenylnitrones (9 and 11) from easily available (R)-2,3-O-cyclohexylideneglyceraldehyde (5) led to an enantiodivergent synthesis of both enantiomers of the dendrobate alkaloid 241D in a sequential two-directional approach involving intramolecular nitrone cycloaddition as the key step. Either of these two nitrones could, in principle, be utilized for the preparation of the title compounds in an enantioconvergent fashion as well. The methodology was extended to prepare an analogue (33) of (-)-241D.

Stereoselective Synthesis of Novel 2-Alkenyl-2,3,4,5-tetrahydro-1,4-epoxy-1-benzazepines and 2-Alkenyl-2,3,4,5-tetrahydro-1H-1-benzazepin-4-ols

New series of polyfunctionalized 2,3,4,5-tetrahydro-1,4-epoxy-1-benzazepines and 2,3,4,5-tetrahydro-1H-1-benzazepin-4-ols substituted at C2 with 2-methylprop-1-enyl, (E)-styryl, and (E)-pent-1-enyl were synthesized starting from the corresponding N-alkenyl-substituted [prenyl, trans-cinnamyl, (E)-hex-2-enyl] 2-allylanilines by a three-step sequence consisting of selective oxidation of aromatic secondary amines, intramolecular nitrone–olefin 1,3-dipolar cycloaddition, and reductive cleavage. The intramolecular 1,3-dipolar cycloaddition is stereoselective favoring the exo-cycloadducts (ratio exo/endo 2–3:1). The stereochemistry was determined by exhaustive NMR analysis and X-ray diffraction.

Causation in a Cascade: The Origins of Selectivities in Intramolecular Nitrone Cycloadditions

The factors controlling chemo-, regio-, and stereoselectivity in a cascade of reactions starting from a bis(cyanoalkenyl)oxime and proceeding via nitrone cycloadditions have been unraveled through a series of density functional theory calculations with several different functionals. Both kinetic and thermodynamic control of the reaction cascade are important, depending upon the conditions. Kinetic control was analyzed by the distortion/interaction model and found to be dictated by differences in distortions of the cycloaddends in the transition states. A new mechanism competing with that originally proposed in the application of these reactions to the histrionicotoxin synthesis was discovered in these studies.