Development of Lewis acid mediated stereoselective synthesis of nitrogen containing heterocycles

University dissertation from Stockholm : Kemi

Author: Åsa Sjöholm Timén; Kth.; [2003]

Keywords: organic chemistry;

Abstract: This thesis deals with the development of syntheticmethodologies for the preparation of enantio- anddiastereomerically enriched nitrogen-containingheterocycles.Asymmetric Lewis acid mediated Diels-Alder reactions with2H-azirines as dienophiles have been studied.Diastereoselective reactions with enantiomerically pureauxiliary-derived 2H-azirines afforded substituted bi- andtri-cyclic azaheterocycles comprising a fusedtetrahydropyridine–aziridine moiety in high yields andselectivities. It was found that the 8-phenylmenthol auxiliarywas superior to Oppolzer’s bornane-2,10-sultam in thesereactions. The influence of various Lewis acids on the reactionoutcome was probed and their presence was crucial forsuccessful reactions. The novel enantioselectiveaza-Diels-Alder reaction of benzyl- 2H-azirine-3-carboxylatewas investigated with a range of chiral Lewis acids andprovided the corresponding cycloadducts in moderate to lowyields and selectivities. The 2H-azirines were synthesized fromthe corresponding acrylates via the vinyl azides. An improvedand general procedure for thermolysis of vinyl azides into2Hazirines was developed.Lewis acid mediated radical cyclizations of substitutedN-chloro-4-pentenyl- and 4- hexenylamines gave thecorresponding pyrrolidines in high yields and in moderate tohigh diastereoselectivities. The reactivity andstereoselectivity were found to be strongly influenced by thesubstituents on the alkenylamine. On the other hand, noapparent correlation between the different Lewis acids appliedand the obtained selectivities was observed. The relativestereochemistry of the cyclic products could be predicted usingthe Beckwith-Houk stereochemical model. The pyrrolidines wererearranged via aziridinium ions, which were ring-opened to thecorresponding piperidines. The efforts to developenantioselective radical cyclizations of cationic aminylradicals proved unsuccessful. Reaction conditions and chiralLewis acids were varied, yet, racemic product mixtures wereobtained. The N-chloro-N-alkenylamines were synthesized in goodyields.Keywords:diastereoselective, enantioselective,alkaloid, Lewis acid, chiral ligand, hetero-Diels-Alderreaction, 2H-azirine, aziridine, tetrahydropyridine, chiralauxiliary, vinyl azide, radical cyclization, cationic aminylradical, pyrrolidine, piperidine, aziridinium ion,N-chloro-N-alkenylamine.

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