6-Substituted 2-azabicyclo[2.2.1]hept-5-enes by nitrogen-directed radical rearrangement: synthesis of an epibatidine analogue with high binding affinity at the nicotinic acetylcholine receptorElectronic supplementary information (ESI) available: details of biological studies. See http://www.rsc.org/suppdata/p1/b1/b107414h/

Abstract

Base-induced isomerisation of epoxide 13 gives an azanortricyclanol 17 which is a precursor for a novel free-radical induced rearrangement to 6-substituted 2-azabicyclo[2.2.1]hept-5-enes 28-31. Compound 31 undergoes selective exo-face hydrogenation to give the 6-substituted 2-azabicyclo[2.2.1]heptane 33 (structure confirmed by X-ray crystallographic analysis). Deprotection of 33 gives epibatidine analogue 2 which has been shown to bind with high affinity at rat brain nicotinic acetylcholine receptors.

Ring-opening, cycloaddition and rearrangement reactions of nitrogen-substituted cyclopropane derivatives

“…The radical method has been applied to the synthesis of an epibatidine analogue (Scheme 51). 152,153 Another application aimed at the stereocontrolled syntheses of kainoid aminoacids is illustrated in Scheme 52. 154 In the latter case, the aminocyclopropane moiety is not part of the starting material but …”

“…Cyclopropane ringopening takes place under typical radical deoxygenation conditions to generate the radical 76, stabilised by the nitrogen atom. Two main types of reactivity are eventually observed: either direct trapping by Bu 3 SnH to produce 2-azabicyclo[2.2.1]hept-5-enes or a further β-fragmentation to produce the radical 77, which finally abstracts a hydrogen atom from Bu 3 SnH to give a dihydropyridine compound(Scheme 50, top) 152,153,154,155,156. The latter reaction pathway operates only when the starting radical precursor bears a radical-stabilising group R 1 (e.g.…”

“…152,153,154,155,156Scheme 51. Synthesis of an epibatidine analogue by a radical ring-opening 152,153. Scheme 52.…”

Radical Deoxygenation of 3-Azatricyclo[2.2.1.02,6]heptan-5-ols to 1,2-Dihydropyridines

“…aryl, Scheme 2). 3 The origin of the selectivity in this rearrangement is probably the stabilisation afforded to the intermediate radical 6 by the a-nitrogen. 4 In the present communication we report on studies originally designed to broaden the scope of the above strategy to give differently substituted 2-azabicyclo[2.2.1]hept-5-enes, but which have also led to an extended radical rearrangement process to give 1,2-dihydropyridines.…”

Radical cascades using enantioenriched 7-azabenzonorbornenes and their applications in synthesis

“…The utility of nitrogen-directed radical rearrangements in the 7-azanorbornene system has been reported previously in relation to the synthesis of a variety of biologically-relevant targets, including epibatidine analogues [ 15 – 16 ], kainic acid [ 17 – 18 ] and ibogamine [ 19 ]. In these studies, the radical step has mainly been carried out in the presence of a relatively fast radical reductant (e.g.…”