1,114 research outputs found
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
Preparation of 1-Substituted Tetrahydro-beta-carbolines by Lithiation-Substitution
A method to prepare 1-substituted N-Boctetrahydro-β-carbolines
was developed by lithiation followed by
electrophilic substitution. The deprotonation to give the
organolithium was optimized by in situ IR spectroscopy and
showed that the Boc group rotates slowly at low temperature.
The chemistry was applied to the synthesis of 9-methyleleagnine
(N-methyltetrahydroharman) and 11-methylharmicine
Regiochemical and Stereochemical Studies of the Intramolecular Dipolar Cycloaddition of Nitrones Derived from Quaternary Aldehydes
Three aldehydes each with a quaternary α-carbon stereocentre bearing an alkenyl, a phenyl, and a methyl ester group were treated with N-methylhydroxylamine. In each case bicyclic isoxazolidine products were formed by condensation to give intermediate nitrones that undergo intramolecular dipolar cycloaddition. The stereoselectivity was influenced by the α-carbonyl substituent, possibly by a hydrogen bond between CO and a nearby CH of the nitrone in the transition state (supported by DFT and X-ray studies), and the regioselectivity was affected by the length of the tether and by the presence of an ester on the alkene dipolarophile
Synthesis of substituted tetrahydroisoquinolines by lithiation then electrophilic quench
Substituted N-tert-butoxycarbonyl (Boc)-1,2,3,4-tetrahydroisoquinolines were prepared and treated with
n-butyllithium in THF at −50 °C to test the scope of the metallation and electrophilic quench. The lithiation
was optimised by using in situ ReactIR spectroscopy and the rate of rotation of the carbamate was
determined. The 1-lithiated intermediates could be trapped with a variety of electrophiles to give good
yields of 1-substituted tetrahydroisoquinoline products. Treatment with acid or reduction with LiAlH4
allows conversion to the N–H or N–Me compound. The chemistry was applied to the efficient total
syntheses of the alkaloids (±)-crispine A and (±)-dysoxyline
Three-component couplings for the synthesis of pyrroloquinoxalinones by azomethine ylide 1,3-dipolar cycloaddition chemistry
1-Methyl-3,4-dihydroquinoxalin-2(1H)-one was heated with a range of aldehydes to generate intermediate azomethine ylides which underwent [3 + 2] cycloaddition reactions with N-methyl or N-phenylmaleimide to give substituted tetrahydropyrroloquinoxalinones. Only one (racemic) stereoisomer was formed in each case and the stereochemical outcome was verified by single crystal X-ray analysis. The products from this multicomponent reaction could be oxidised with DDQ to the pyrroloquinoxalinones
Synthesis of pyrrolo[1,2-a]quinolines by formal 1,3-dipolar cycloaddition reactions of quinolinium salts
Quinolinium salts, Q+-CH2-CO2Me Br− and Q+-CH2-CONMe2 Br− (where Q = quinoline), were prepared from quinolines. Deprotonation of these salts with triethylamine promoted the reaction of the resulting quinolinium ylides (formally azomethine ylides) with electron-poor alkenes by conjugate addition followed by cyclization or by [3 + 2] dipolar cycloaddition. The pyrroloquinoline products were formed as single regio- and stereoisomers. These could be converted to other derivatives by Suzuki–Miyaura coupling, reduction or oxidation reactions
Synthesis of the tricyclic core of manzamine A
An efficient synthetic approach to the core structure of the manzamine alkaloids is reported, particularly in relation to incorporating a one-carbon unit in ring B from which the aldehyde in ircinal A or the beta-carboline unit in manzamine A could potentially be generated. The key steps involve a Johnson–Claisen rearrangement, enolate alkylation, dithiane alkylation and a stereoselective intramolecular dipolar cycloaddition of an azomethine ylide, which provided the desired tricyclic ABC core structure
Synthesis of pyrrolo[1,2-a]quinolines by formal 1,3-dipolar cycloaddition reactions of quinolinium salts
Quinolinium salts, Q+-CH2-CO2Me Br− and Q+-CH2-CONMe2 Br− (where Q = quinoline), were prepared from quinolines. Deprotonation of these salts with triethylamine promoted the reaction of the resulting quinolinium ylides (formally azomethine ylides) with electron-poor alkenes by conjugate addition followed by cyclization or by [3 + 2] dipolar cycloaddition. The pyrroloquinoline products were formed as single regio- and stereoisomers. These could be converted to other derivatives by Suzuki–Miyaura coupling, reduction or oxidation reactions
Photocatalysis and kinetic resolution by lithiation to give enantioenriched 2-arylpiperazines
Piperazines are important heterocycles in drug compounds. We report the asymmetric synthesis of arylpiperazines by photocatalytic decarboxylative arylation (metallaphotoredox catalysis) then kinetic resolution using n-BuLi/(+)-sparteine. This gave a range of piperazines with very high enantioselectivities. Further functionalizations gave enantioenriched 2,2-disubstituted piperazines, and either N-substituent can be removed selectively. Late-stage functionalizations of enantioenriched piperazine derivatives were demonstrated, including synthesis of a drug compound with glycogen synthase kinase (GSK)-3β inhibitor activity with potential for treating Alzheimer’s disease
Synthesis of Spirocyclic Amines by Using Dipolar Cycloadditions of Nitrones
Aliphatic ketones containing a chloride and alkene
were heated with hydroxylamine to promote cascade, tandem
condensation to oximes, cyclization to nitrones, and 1,3-dipolar
cycloaddition to tricyclic isoxazolidines as single stereoisomers.
Single regioisomers were obtained when three atoms linked the
ketone and dipolarophile to give five-membered rings but
mixtures resulted with four atoms in the tether unless a terminal
ester was located on the alkene. The N−O bond in the products could be reduced to give spirocyclic amines and diamines
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