Intramolecular Nitrone Cycloaddition Research Articles

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.

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.

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

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.

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.

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.

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.

Synthesis of Novel Isoxazolidines and Medium-Ring Heterocycles Oxazocines and Oxazonines

A number of novel oxa-bridged and methylene oxa-bridged bicyclic isoxazolidines have been synthesized using intramolecular nitrone cycloaddition. The reductive cleavage of N-O bonds of the isoxazolidines to provide novel medium-ring heterocycles oxazocines and oxazonines is also described. Keywords: Isoxazolidines, oxazocines, oxazonines, amino alcohols, medium-ring heterocycles, oxa-bridged, methylene, nitrone, cycloaddition, benzoxazocine

Dehydrative intramolecular nitrone cycloaddition in confined aqueous media: a green chemical route to cis-fused chromano[4,3-c]isoxazoles

An efficient synthetic route to the formation of cis-fused chromano[4,3-c]isoxazoles via dehydrative intramolecular 1,3-dipolar nitrone cycloaddition in organized aqueous media in the presence of a surfactant (viz. CTAB) as catalyst was developed, which indeed appeared to be green and a more sustainable method than the existing methods with the additional advantage of easy isolation of products.

ChemInform Abstract: Expeditious Synthesis of Aminocyclopentitols from D-Ribose via Intramolecular Nitrone Cycloaddition.

The synthesis of 4α-aminocyclopentane-1α, 2β,3β-triol (a key-intermediate in the preparation of carbocyclic nucleosides) and its N-substituted derivatives, has been achieved by the Intramolecular nitrone cycloadditions of a γ-unsaturated aldehyde, easily accessible from D-ribose, followed by reductive N–O bond cleavage in the resulting bicyclic oxazanes.

Locked Nucleosides Based on Oxabicyclo[3.2.1]octane and Oxabicyclo[2.2.1]heptane Skeletons

Intramolecular nitrone cycloaddition (INC) reaction on a d-glucose derived substrate carrying an allyl group at C-1 and an enose-nitrone at C-5 or an aldehyde-nitrone at C-1 and vinyl group at C-4 furnished a tricyclo[6.2.1.0(2,6)]undecane or a tricyclo[5.2.1.0(2,6)]decane ring structure. These tricycles were converted to bicylic nucleosides with oxabicyclo[3.2.1]octane and oxabicyclo[2.2.1]heptane rings in three steps. An oxabicyclo[3.2.1]octane ring compound could alternatively be formed by RCM reaction between C-1-allyl and C-4-vinyl moieties and transformed to nucleoside analogues through a nucleophilic substitution reaction. Participation of a neighboring benzyl ether substituent in one case paved the way for an enantiodivergent synthesis.

ChemInform Abstract: A Regio‐ and Diastereoselective Intramolecular Nitrone Cycloaddition for Practical 3‐ and 2,3‐Disubstituted Piperidine Synthesis from γ‐Butyrolactone.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

A Regio- and Diastereoselective Intramolecular Nitrone Cycloaddition for Practical 3- and 2,3-Disubstituted Piperidine Synthesis from γ-Butyrolactone

A fast and efficient route for diversity-oriented synthesis of 3- and 2,3-disubstituted piperidines, featuring an intramolecular nitrone cycloaddition with high regio- and diastereoselectivity, was achieved in six steps and 36-66% overall yield from commercially available gamma-butyrolactone or 1,4-butanediol. A new N-alkenyl nitrone enoate was used in this intramolecular nitrone cycloaddition, and the regioselectivity, diastereoselectivity, and reversibility of this cycloaddition were investigated.

Synthesis of Oxepane Ring Containing Monocyclic, Conformationally Restricted Bicyclic and Spirocyclic Nucleosides from d-Glucose: A Cycloaddition Approach

Carbohydrate-derived substrates having (i) C-5 nitrone and C-3-O-allyl, (ii) C-4 vinyl and a C-3-O-tethered nitrone, and (iii) C-5 nitrone and C-4-allyloxymethyl generated tetracyclic isoxazolidinooxepane/-pyran ring systems upon intramolecular nitrone cycloaddition reactions. Deprotection of the 1,2-acetonides of these derivatives followed by introduction of uracil base via Vorbrüggen reaction condition and cleavage of the isooxazolidine rings as well as of benzyl groups by transfer hydrogenolysis yielded an oxepane ring containing bicyclic and spirocyclic nucleosides. The corresponding oxepane based nucleoside analogues were prepared by cleavage of isoxazolidine and furanose rings, coupling of the generated amino functionalities with 5-amino-4,6-dichloropyrimidine, cyclization to purine rings, and finally aminolysis.

Synthesis of enantiopure 4-amino-3-hydroxymethyl-tetrahydroquinolines via an intramolecular nitrone cycloaddition

Enantiopure 4-amino-3-hydroxymethyl-1,2,3,4-tetrahydroquinolines are synthesized by using an intramolecular cycloaddition of chiral nitrones prepared from aldehydes 5 and ( R)-α-(hydroxymethyl)benzylhydroxylamine. Reaction times of the nitrone cycloaddition were optimized by activation under MW-assisted conditions. The absolute configuration of the products was determined by X-ray analysis.

Experimental and theoretical evidences of 2-aza-Cope rearrangement of nitrones

Both the intramolecular cycloaddition of diastereomeric homochiral N-alkenyl nitrones and the corresponding theoretical calculations using DFT and ab initio methods provided evidences of a thermal [3,3] sigmatropic rearrangement of the nitrones with a complete chirality transfer.