Synthesis of new 7-azabicyclo[2.2.1]heptane derivatives

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-1-yl)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 7-azabicyclo[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.

Mechanistic Analysis of Intramolecular Free Radical Reactions toward Synthesis of 7-Azabicyclo[2.2.1]heptane Derivatives

“…Concerning the intramolecular free radical cyclization of sulfonamides, the tributyltin hydride mediated cyclization of 5 R provided the ring-closure derivative 7 in 51% yield . This is not an unexpected result since the computed length of N−S (1.695 Å) and S−C (1.793 Å) single bonds allows an easy access to the transition state, with a minor geometric distortion (N pyramidalization, +1.5°; closing of the N−S−C bond angle, −3.5°, on going from 5 R to TS 5 , Figure ) and reduces the annular tension of the forming cycle.…”

“…In the GC/MS analysis of the reaction crude three compounds were detected ( 16 , 6 , 17 ) in a 3:31:5 ratio. After chromatography we were only able to isolate and characterize an inseparable mixture of 16 and 6 in a 1:5.6 ratio (GC/MS) …”

“…We have studied by DFT methods the mechanisms of intramolecular free radical reactions for the synthesis of conformationally constrained epibatidine analogues . Computational analyses have been carried out to explain the mechanism of this reaction and the key effect of the 7-nitrogen protecting group as tethering chain on the outcome of these cyclizations.…”

“…This justifies that carbamates or amides inhibit the process and yield major reduced, uncyclized, reaction products, as the limited chain flexibility gives rise to a high activation barriers. Unlike these groups, the N -sulfonyl and the N -arylmethyl functional motifs, inherently flexible, involve a lower activation barrier for the cyclization than for the reduction, which is supported by the fact that they afforded major cyclized products . Therefore, theoretical calculations should be a valuable tool to select proper precursors for future synthesis of new epibatidine analogues.…”

“…Taking into account these precedents, we decided to synthesize and submit to cyclization radical precursors 1 − 5 (Figure ). Unfortunately, successful results have only been observed for precursors 4 and 5 to give epibatidine analogues 6 and 7 (Figure ), respectively . When this work was in progress, Armstrong and co-workers reported what appears to be the first intramolecular cyclization of a precursor in this series, namely, exo -2-bromo-7-(toluene-4-sulfonyl)-7-azabicyclo[2.2.1]heptane …”