Synthesis of new 7-azabicyclo[2.2.1]heptane derivatives

José Marco-Contelles,Mónica Álvarez-Pérez,Abdelouahid Samadi,Elena Soriano,Elena Gómez-Sánchez,Carolina Valderas,Christopher A Ramsden

doi:10.3998/ark.5550190.0011.307

Abstract

The synthesis of new 7-azabicyclo[2.2.1]heptane derivatives has been achieved in a four-step synthetic sequence, starting from readily available cyclohex-3-enecarboxylic acid, Curtius reaction, stereoselective bromination leading to major benzyl(cis-3,trans-4-dibromocyclohex-1yl)carbamates (amides or sulfonamides), followed by NaH-mediated intramolecular cyclization. The synthesis and free radical cyclization of precursors 4-7, as well as the synthesis of a conformationally constrained epibatidine analogue 3 exploiting the reactivity of the 7azabicyclo[2.2.1]hept-2-yl radical in intramolecular reactions, are described. The N-sulfonyl functional motif is the only one to afford a cyclized product when incorporated in the radical precursor.

Highlights

Epibatidine 1,1 an alkaloid isolated from the skin of the Ecuadorian poison frog Epipedobates tricolor,[2] is a powerful analgesic agent 200 times more potent than morphine, with high affinity for the nicotinic acetylcholine receptor.[3]
We have recently described the synthesis of 7-substituted exo-2-bromo-7azabicyclo[2.2.1]heptane derivatives[8,9] following a potent method based on a four-step synthetic sequence, starting from readily available cyclohex-3-enecarboxylic acid, Curtius reaction, stereoselective bromination leading to major tert-butylcarbamates,[10] followed by NaH-mediated intramolecular cyclization (Scheme 1).[11]
In Scheme 2 we show our general approach for the synthesis of this type of compounds, based on the intramolecular free radical cyclization of species II, readily available from precursors III bearing convenient radical acceptors at C7 and good leaving groups at C2 (Scheme 2)

Summary

Introduction

Epibatidine 1,1 an alkaloid isolated from the skin of the Ecuadorian poison frog Epipedobates tricolor,[2] is a powerful analgesic agent 200 times more potent than morphine, with high affinity for the nicotinic acetylcholine receptor (nAChR).[3].

Results

Conclusion