Intramolecular Nitrone-alkene Cycloaddition 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.

Total synthesis of pleosporol A and its stereoisomers

Abstract The cyclohexenone derivatives pleosporols A, B and stemfolone B were reported as novel antibacterial agents. In this study, we reported the first total synthesis of pleosporol A and its stereoisomers from arabinose, utilizing intramolecular nitrone-alkene cycloaddition and Hofmann elimination under Swern condition for constructing the cyclohexene ring.

Total Synthesis of Lycopodium Alkaloids Palhinine A and Palhinine D.

The first total syntheses of Lycopodium alkaloids palhinine A, palhinine D, and their C3-epimers have been divergently achieved through the use of a connective transform to access a pivotal hexacyclic isoxazolidine precursor. A microwave-assisted regio- and stereoselective intramolecular nitrone-alkene cycloaddition was tactically orchestrated as a key step to install the crucial 10-oxa-1-azabicyclo[5.2.1]decane moiety embedded in the conformationally rigid isotwistane framework, demonstrating the feasibility of constructing the highly strained medium-sized ring by introduction of an oxygen bridging linker to relieve the transannular strain in the polycyclic scaffold. Subsequent N-O bond cleavage provided the synthetically challenging nine-membered azonane ring system bearing the requisite C3 hydroxyl group. Late-stage transformations featuring a chemo- and stereoselective reduction of the pentacyclic β-diketone secured the availability of our target molecules.

Electronic Effects on the cis/trans Selectivity in Formation of Isoxazolidine-Fused Eight-Membered Ring via an Intramolecular Nitrone-Alkene Cycloaddition

An intramolecular nitrone-alkene cycloaddition involving in situ generated nitrones demonstrated reaction profiles different from those previously reported for pyrimidine system. Tuning the electron density of the benzene ring had a significant effect on cis/trans selectivity. These reactions were useful for the synthesis of novel tricyclic hexahydrobenzo[b]isoxazolo[3,4-f][1, 4]diazocin-4(1H)-ones and hexahydroisoxazolo[3,4-f]pyrido[3,2-b][1, 4]diazocin-4(1H)-one under mild reaction conditions in good yields

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.

DFT study on the intramolecular nitrone–alkene cycloaddition reaction of the N-3-alkenylnitrone

Intramolecular nitrone–alkene cycloaddition (INAC) of the N-alkenylnitrone represents an appealing method for the syntheses of bicyclic and polycyclic isoxazolidines. In this paper, we have conducted the systematic theoretical study on the regioselectivity in the INAC reactions of various N-3-alkenylnitrones which carry synthetically relevant substituents by using DFT method. Substitution at the C2- or C6-position exhibits the Z-selectivity almost exclusively, while substitution at the C1-position enhances the E-selectivity. Marcus theory analyses show the involvement of both the thermodynamic and intrinsic contributions in determining the Z-selectivity. In addition, the introduction of the substituents on the olefinic bond can reduce the rate of the INAC reaction. However, an additional method, namely the incorporation of an aromatic ring into the N-3-alkenylnitrone backbone at the C3- and C4-positions, has been provided. This method can not only enhance the Z-selectivity but also increase the rate of the INAC reaction.

Facile and Enantiospecific Syntheses of (6S,7R)-6-Chloro-7-benzyloxy-, (7S)-Halo-, and (7S)-Hydroxy-cocaine and Natural (−)-Cocaine from d-(−)-Ribose

First syntheses of C6,7 and C7 enantiopure cocaine analogues were achieved from D-(-)-ribose via a trans-acetonide controlled endo-selective intramolecular nitrone-alkene cycloaddition (INAC) as the key step. This synthetic scheme allows practical preparation of cocaine analogues for bioevaluation as potential candidates for the treatment of cocaine addiction and as potential conjugates for immunotherapy.

Synthesis of ent-gabosine E from d-mannose by intramolecular nitrone–olefin cycloaddition

Intramolecular nitrone–olefin cycloaddition in a mannose template followed by N–O cleavage, quaternization of the resulting amine, and finally oxidative elimination of the amino group affords, after deprotection, ent-gabosine E in enantiomerically pure form.

Stereo‐ and Regioselectivity in an Intramolecular Nitrone–Alkene Cycloaddition of Hept‐6‐enoses with a trans‐Acetonide Blocking Group

From sugar to cycloadduct: The effect of the trans-acetonide blocking group and the stereochemistry of the substituents on the regio- and stereoselectivity in the intramolecular nitrone-alkene cycloaddition (INAC) reaction of hept-6-enoses (see scheme) is reported and studied by using theoretical analysis.The positional effect of the trans-acetonide blocking group and the effect of the stereochemistry of the substituents on the regio- and stereoselectivity in intramolecular nitrone-alkene cycloaddition (INAC) reactions of hept-6-enoses are reported. Hept-6-enoses with a 2,3-trans-acetonide group were reacted with N-alkyl hydroxylamine to give a mixture of exo and endo cycloadducts (cyclohexanols and cycloheptanols, respectively). Complete formation of endo cycloadducts (cycloheptanols) was realized for the INAC reaction of hept-6-enoses containing a 3,4-trans-O-isopropylidene ring. Similarly, reaction of a hept-6-enose possessing a 4,5-trans-acetonide group surprisingly afforded exo cycloadducts (cyclohexanols) exclusively. The regio- and stereochemical outcomes of these reactions were rationalized on the basis of transition-state energies obtained by computation.

ChemInform Abstract: Intramolecular Nitrone—Olefin Cycloaddition of D‐Glucose‐Derived Allylic Alcohol: Synthesis of New Aminocyclohexitols.

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.

Intra-molecular nitrone–olefin cycloaddition of d-glucose derived allylic alcohol: synthesis of new aminocyclohexitols

Diastereo- and regioselelective intra-molecular nitrone–olefin cycloaddition reaction of in situ generated N-benzylnitrones, obtained from d-glucose derived precursors 5a/ 5b furnished dihydroxy functionalized isoxazolidines. The N– O bond reductive cleavage and removal of N/ O-benzyl groups led to the formation of stereochemically well defined aminocyclohexitols.

Trans‐Acetonide Controlled endo‐Selective Intramolecular Nitrone—Alkene Cycloaddition of Hept‐6‐enoses: A Facile Entry to Calystegines, Tropanes, and Hydroxylated Aminocycloheptanes.

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, please click on HTML or PDF.

Trans-Acetonide Controlled endo-Selective Intramolecular Nitrone−Alkene Cycloaddition of Hept-6-enoses: A Facile Entry to Calystegines, Tropanes, and Hydroxylated Aminocycloheptanes

High-yielding endo-selective intramolecular nitrone-alkene cycloaddition (INAC) reactions of hept-6-enoses controlled by a trans-acetonide to give bridged bicyclo[4.2.1]isoxazolidines exclusively are realized for the first time. The cycloadducts were readily transformed into calystegine, tropane, and hydroxylated aminocycloheptane frameworks. [reaction: see text].

Experimental and Theoretical Studies on Stereo- and Regioselectivity in Intramolecular Nitrone−Alkene Cycloaddition of Hept-6-enoses Derived from Carbohydrates

The effect of blocking groups and stereochemistry of the substituents on the regio- and stereoselectivity in intramolecular nitrone-alkene cycloaddition (INAC) of hept-6-enoses are reported. L-ribo-Hept-6-enose 12 and D-lyxo-hept-6-enose 15, both containing a 2,3-O-isopropylidene blocking group, and L-xylo-hept-6-enose 23 and D-arabino-hept-6-enose 30, both with a 2,3-O-trans-diacetal blocking group, were prepared from D-ribose and D-arabinose, respectively. With N-alkyl hydroxylamine, lactols 12 and 15 underwent an INAC reaction to give cis-fused isoxazolidines exclusively whereas lactols 23 and 30 gave a mixture of cis-, trans-fused isoxazolidines (cyclohexanols) and bridged isoxazolidines (cycloheptanols). With the 2,3-O-trans-diacetal protecting group, the bridged bicyclo[4.2.1]isoxazolidines (cycloheptanols), via the endo mode of INAC cyclization, were synthesized for the first time from unbranched sugar derivatives 23 and 30. The stereochemical outcomes of these reactions were rationalized on the basis of transition state energies obtained by computation. The present INAC showed trivial temperature, but significant solvent dependence. For lactols 23 and 30, performing the INAC in 2-propanol gave the best yields of fused isoxazolidines (cyclohexanols) whereas in dichloromethane afforded the best yields of bridged isoxazolidines (cycloheptanols).

Diastereoselective Route to Novel Fused or Bridged Tricyclic β‐Lactams Through Intramolecular Nitrone—Alkene Cycloaddition of 2‐Azetidinone‐Tethered Alkenylaldehydes — Synthetic Applications to Carbacephams and Cyclic β‐Amino Acid Derivatives.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Diastereoselective Route to Novel Fused or Bridged Tricyclic β‐Lactams through Intramolecular Nitrone–Alkene Cycloaddition of 2‐Azetidinone‐Tethered Alkenylaldehydes – Synthetic Applications to Carbacephams and Cyclic β‐Amino Acid Derivatives

AbstractA convenient, regio‐ and stereoselective direct route to optically pure unusually fused or bridged tricyclic β‐lactams has been developed by use of intramolecular nitrone–alkene cycloaddition (INAC) reactions of easily available monocyclic 2‐azetidinone‐tethered alkenylaldehydes as the key synthetic step. The regioselectivity of the cycloaddition can be tuned by moving the alkene substituent from N1 to C3 on the 2‐azetidinone ring. In addition, some simple, interesting transformations were tested on representative examples of the different types of tricyclic systems prepared, in order to demonstrate their potential as intermediates in the preparation of differently polyfunctionalized compounds, including carbacepham derivatives and related unconventional bicyclic systems containing medium‐sized rings fused to the β‐lactam nucleus, as well as several types of cyclic β‐amino acid derivatives. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Stereo- and regiospecific formation of a highly functionalized bridgehead tricyclic sultam

Tethering of a nitrone moiety to an olefin containing endocyclic sultam results in high yielding spontaneous intramolecular nitrone–olefin cycloaddition. The reaction proceeds with complete regio- and stereospecific control to establish three new chiral centers in the tricyclic products which incorporate an unusual bridgehead sultam motif. A transition state model for the remarkable regio- and stereochemistry is supported by NMR analysis and X-ray crystal diffraction. Three sites of chemical diversity are highlighted which make the tricyclic template an attractive combinatorial scaffold.

Structural elucidation and complete assignment of a novel class of sulfonamides: bridgehead tricyclic sultams

AbstractEndocyclic sulfonamide templates bearing both an exocyclic ketone function and an internal olefin underwent reaction with a variety of hydroxylamines to effect an intramolecular nitrone–olefin cycloaddition to afford a new class of compounds suitable for derivatization by high‐throughput medicinal chemistry. Structural elucidation via complete assignment of the 1H and 13C NMR spectra of this new class of compounds was achieved using gradient‐COSY, gradient heteronuclear multiple quantum‐coherence spectroscopy and gradient heteronuclear multiple bond correlation spectroscopy. Additionally, double pulsed field gradient spin echo–nuclear Overhauser effect experiments were carried out in order to study the spatial conformation of this new type of molecule and assess the stereo‐ and regio‐selectivity of the chemical transformation. The unequivocal molecular framework and structural conformation was confirmed by X‐ray diffraction. Copyright © 2002 John Wiley & Sons, Ltd.

Concise, Divergent β-Lactam-based Route to Indolizidine and Quinolizidine Derivatives via Sequential Regio- and Stereocontrolled Intramolecular Nitrone-alkene Cycloadditions

A novel, concise, divergent methodology to both indolizidine and quinolizidine systems based on the sequential regio- and stereocontrolled intramolecular nitrone-alkene cycloaddition (INAC) reactions of 2-azetidinone-tethered alkenylaldehydes is reported.

1,3]-Dipolar intramolecular nitrone olefin cycloaddition reaction of a sugar-derived α,β-unsaturated ester: a new diastereo- and regioselective synthesis of an aminocyclopentitol

The reaction of hemiacetal 2a , from the sugar derived α,β-unsaturated ester 1a , with N-benzylhydroxylamine hydrochloride in situ generates an N-benzylnitrone as a 1,3-dipole, which spontaneously undergoes diastereo- and regioselective intramolecular nitrone olefin cycloaddition to afford a hydroxy functionalised 4- exo-ethoxycarbonyl-3-oxa-2-azabicyclo[3.3.0]octane system, a precursor to a hitherto unknown aminocyclopentitol derivative.