An Epoxide Rearrangement - Radical Rearrangement Approach to 6-Substituted 2-Azabicyclo[2.2.1]-5-heptenes: Synthesis of an Epibatidine Analogue

Abstract

Base-induced isomerisation of epoxide 9 gives an azanortricyclanol 10 which is a precursor for a novel free-radical induced rearrangement to 6-substituted 2-azabicyclo[2.2.1]-5-heptenes 14a-c; 14c (R = 6-chloro-3-pyridinyl) is converted to the epibatidine analogue 2.In 1992 Daly and coworkers reported the isolation and structural elucidation of the alkaloid epibatidine 1. 1 Epibatidine has attracted considerable attention from the scientific community due to its novel structure combined with the fact that it is a highly potent non-opioid analgesic nicotinic acetylcholine receptor (nAChR) agonist. 2 Unfortunately, epibatidine 1 is toxic or even lethal at doses only slightly higher than its effective analgesic dose, however it is a significant therapeutic lead in the important search for nAChR modulators having a wider separation between antinociceptive and toxic effects. 3 In this context we considered a structurally interesting target would be endo-6-(6-chloro-3-pyridinyl)-2-azabicyclo[2.2.1]-heptane (2), since it represents an isomer of epibatidine in which the nitrogen in the rigid bicyclo[2.2.1]heptyl framework is translocated from the 7-to the 2-position but maintains the same connectivity and similar relative orientation to the chloropyridyl substituent. We envisaged the epibatidine analogue 2 being derived from exo-selective hydrogenation of a 6-substituted 2-azabicyclo[2.2.1]-5-heptene 3 and describe here our preliminary results on a method to prepare such systems and a synthesis of 2.The 2-azabicyclo[2.2.1]heptyl ring system can be most easily prepared by aza Diels-Alder reaction using cyclopentadiene. 4 Although exo-5-aryl substituted 2-azabicyclo[2.2.1]heptanes have recently been prepared by such a cycloaddition followed by a reductive Heck reaction, 5 6-substituted systems are not accessible by this pathway. 6 Our strategy (Scheme 1) employs a rearrangement via lithiation of an achiral epoxide (4 to 5) (making it potentially amenable to asymmetric synthesis by enantioselective deprotonation), 7 followed by a radical rearrangement (6 to 7). A related radical rearrangement (8-aza-to 6-azabicyclo[3.2.1]oct-2-en-7-yl radical) was reported by Rigby and Pigge in 1996. 8 In order to examine this chemistry, the achiral epoxide 9 was prepared by epoxidation 9 (76%) 10 of the known 11 alkene 8 (available in three steps from N-Boc pyrrole and tosyl ethyne) (Scheme 2). Base-induced rearrangement of the epoxide 9 using LDA gave azanortricyclanol 10 (52%). 12 Radical deoxygenation 13 of azanortricyclanol 10 gave the known 5 2-azabicyclo[2.2.1]heptene 11 (60%) as the only isolated product. The well-studied (all carbon) norbornenyl-nortricyclyl radical equilibrium is known to produce a mixture of norbornene and nortricyclene on reduction with Bu 3 SnH. 14 In the present case the radical 7 (R = H) which leads to the 2-aza alkene 11 may be strongly preferred due to a stabilising effect of the radical by the N-Boc group and/or a larger CH-N-CH angle in 7 (compared with 6) which promotes amide-type resonance. 15 Schem...

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 …”

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

“…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.…”

Expanding the Utility of Lithiated Epoxides and Aziridines in Synthesis

“…Radical deoxygenation of the methyl oxalate of 21 led not to a 7-azabicycle, but rather to the 2-azabicyclic alkene 22. 26,27 The selective rearrangement of 21 to 22 constituted a starting point for our investigations on nitrogen-directed radical rearrangements (though that is another story). 28 Alkene hydrogenation and subsequent nitrogen deprotection of 22 gave the epibatidine analogue 23, which proved to be a marginally more active analgesic than the natural product itself.…”

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.…”